The NM_000546.6 :c.659A>G variant in TP53 is a missense variant predicted to cause substitution of Tyrosine by Cysteine at amino acid 220 (p.Tyr220Cys). This variant has been reported in 9 unrelated probands and/or families meeting Classic and/or Revised Chompret criteria. Based on this evidence, this variant scores 6.5 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMIDs: 20028212, 9242456, 19101993, 18307025, 20805372, 21761402, 27714481, 10589545, 10432928, 8118819, ClinVar SCV: SCV000183774.8, Internal lab contributors). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 1 individual with an LFS-associated cancer totaling 2 phenotype points (PS2_Moderate; PMID: 18307025). The variant has been reported to segregate with LFS-associated cancers in ≥ 7 meioses from 5 families (PP1_Strong; PMIDs: 20028212, 1910993, 10432928, 8118819, 27714481). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, ClinVar GTRs, SCV000183774.8). This variant has an allele frequency of 0.000005932 (7/1179948 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PMIDs: 12826609, 30224644, 29979965) (PS3). This variant has 127 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (≥ 10 somatic occurrences, PMID: 30311369) (PM1). Computational predictor scores (BayesDel = 0.5625; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4, PS2_Moderate, PP1_Strong, PM2_Supporting, PS3, PM1, PP3_Moderate, PP4_Moderate (Bayesian Points: 21 points; VCEP specifications version 2.0; 7/24/2024)
NM_000546.6(TP53):c.659A>G (p.Tyr220Cys)
Germline
Reviewed by expert panel
Help
Reviewed by expert panel. Learn more about how ClinVar calculates review status.
Pathogenic
for
Li-Fraumeni syndrome
Classification is based on the expert panel submission
Aug 2024 by
ClinGen TP53 Variant Curation Expert Panel, ClinGen
Help
FDA Recognized Database
The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Somatic
Clinical impact
Help
criteria provided, single submitter. Learn more about how ClinVar calculates review status.
5 out of 5 submissions contributed to this classification
Help
The aggregate somatic clinical impact for this variant for one or more tumor types, using the AMP/ASCO/CAP terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
5
Somatic
Oncogenicity
Help
criteria provided, single submitter. Learn more about how ClinVar calculates review status.
Oncogenic
This classification is based on the single submission received
Help
The aggregate oncogenicity classification for this variant for one or more tumor types, using the ClinGen/CGC/VICC terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
1
Variant Details
- Identifiers
-
NM_000546.6(TP53):c.659A>G (p.Tyr220Cys)
Variation ID: 127819 Accession: VCV000127819.104
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17p13.1 17: 7674872 (GRCh38) [ NCBI UCSC ] 17: 7578190 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jan 7, 2017 Apr 25, 2026 Aug 5, 2024 Somatic - Clinical impact Nov 22, 2025 Nov 22, 2025 Jan 15, 2025 Somatic - Oncogenicity Aug 11, 2024 Mar 11, 2025 Mar 4, 2025 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000546.6:c.659A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Tyr220Cys missense NM_000546.5(TP53):c.659A>G NM_001126112.3:c.659A>G NP_001119584.1:p.Tyr220Cys missense NM_001126113.3:c.659A>G NP_001119585.1:p.Tyr220Cys missense NM_001126114.3:c.659A>G NP_001119586.1:p.Tyr220Cys missense NM_001126115.2:c.263A>G NP_001119587.1:p.Tyr88Cys missense NM_001126116.2:c.263A>G NP_001119588.1:p.Tyr88Cys missense NM_001126117.2:c.263A>G NP_001119589.1:p.Tyr88Cys missense NM_001126118.2:c.542A>G NP_001119590.1:p.Tyr181Cys missense NM_001276695.3:c.542A>G NP_001263624.1:p.Tyr181Cys missense NM_001276696.3:c.542A>G NP_001263625.1:p.Tyr181Cys missense NM_001276697.3:c.182A>G NP_001263626.1:p.Tyr61Cys missense NM_001276698.3:c.182A>G NP_001263627.1:p.Tyr61Cys missense NM_001276699.3:c.182A>G NP_001263628.1:p.Tyr61Cys missense NM_001276760.3:c.542A>G NP_001263689.1:p.Tyr181Cys missense NM_001276761.3:c.542A>G NP_001263690.1:p.Tyr181Cys missense NC_000017.11:g.7674872T>C NC_000017.10:g.7578190T>C NG_017013.2:g.17679A>G LRG_321:g.17679A>G LRG_321t1:c.659A>G LRG_321p1:p.Tyr220Cys P04637:p.Tyr220Cys - Protein change
- Y181C, Y220C, Y88C, Y61C
- Other names
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p.Y220C:TAT>TGT
NM_000546.6(TP53):c.659A>G
- Canonical SPDI
- NC_000017.11:7674871:T:C
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD), exomes 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD) 0.00001
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| TP53 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3886 | 3987 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Dec 8, 2025 | RCV000115731.20 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Aug 1, 2025 | RCV000213055.53 | |
| Pathogenic (6) |
reviewed by expert panel
|
Aug 5, 2024 | RCV000232050.23 | |
| Pathogenic (1) |
criteria provided, single submitter
|
- | RCV000433936.7 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Dec 1, 2018 | RCV000785544.4 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 15, 2024 | RCV001310212.5 | |
| Pathogenic (1) |
no assertion criteria provided
|
Mar 19, 2021 | RCV001527468.4 | |
| Pathogenic (1) |
no assertion criteria provided
|
Aug 21, 2021 | RCV001579295.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 10, 2022 | RCV002490776.2 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jul 1, 2021 | RCV003162539.3 | |
|
TP53-related disorder
|
Pathogenic (2) |
criteria provided, single submitter
|
Jan 30, 2023 | RCV003407499.5 |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 3, 2023 | RCV003460829.1 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
- | RCV003997298.1 | |
| click to load more conditions click to collapse | ||||
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
Expand all rows
Collapse all rows
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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|---|---|---|---|---|---|
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Pathogenic
(Aug 05, 2024)
C
Contributing to aggregate classification
|
reviewed by expert panel
|
Li-Fraumeni syndrome
(Autosomal dominant inheritance)
|
ClinGen TP53 Variant Curation Expert Panel, ClinGen
FDA Recognized Database
Accession: SCV001142546.2 First in ClinVar: Jan 12, 2020 Last updated: Aug 18, 2024 |
Comment:
show
The NM_000546.6 :c.659A>G variant in TP53 is a missense variant predicted to cause substitution of Tyrosine by Cysteine at amino acid 220 (p.Tyr220Cys). This variant has been reported in 9 unrelated probands and/or families meeting Classic and/or Revised Chompret criteria. Based on this evidence, this variant scores 6.5 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMIDs: 20028212, 9242456, 19101993, 18307025, 20805372, 21761402, 27714481, 10589545, 10432928, 8118819, ClinVar SCV: SCV000183774.8, Internal lab contributors). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 1 individual with an LFS-associated cancer totaling 2 phenotype points (PS2_Moderate; PMID: 18307025). The variant has been reported to segregate with LFS-associated cancers in ≥ 7 meioses from 5 families (PP1_Strong; PMIDs: 20028212, 1910993, 10432928, 8118819, 27714481). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, ClinVar GTRs, SCV000183774.8). This variant has an allele frequency of 0.000005932 (7/1179948 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PMIDs: 12826609, 30224644, 29979965) (PS3). This variant has 127 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (≥ 10 somatic occurrences, PMID: 30311369) (PM1). Computational predictor scores (BayesDel = 0.5625; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4, PS2_Moderate, PP1_Strong, PM2_Supporting, PS3, PM1, PP3_Moderate, PP4_Moderate (Bayesian Points: 21 points; VCEP specifications version 2.0; 7/24/2024) (less)
Observation: 1
Collection method: curation
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: curation
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Aug 01, 2018)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000888669.2
First in ClinVar: Dec 15, 2018 Last updated: Jan 01, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Apr 10, 2022)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Familial cancer of breast
Colorectal cancer Hepatocellular carcinoma Glioma susceptibility 1 Li-Fraumeni syndrome 1 Adrenocortical carcinoma, hereditary Bone osteosarcoma Familial pancreatic carcinoma Choroid plexus papilloma Nasopharyngeal carcinoma Basal cell carcinoma, susceptibility to, 7 Bone marrow failure syndrome 5 |
Fulgent Genetics, Fulgent Genetics
Accession: SCV002797313.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(Jul 27, 2022)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
GeneDx
Accession: SCV000149640.17
First in ClinVar: May 17, 2014 Last updated: Mar 04, 2023 |
Comment:
show
Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression activity (Kato 2003, Malcikova 2010, Monti 2011, Giacomelli 2018, Kotler 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23365691, 17015838, 22923379, 27470445, 27503952, 28091804, 28679691, 27322648, 29853601, 20407015, 26619011, 24487413, 20128691, 17606709, 24395441, 19367569, 24573247, 21343334, 18307025, 19101993, 8118819, 10432928, 15977174, 20028212, 20805372, 21761402, 23484829, 24702488, 27840695, 27714481, 23315175, 28861920, 29099488, 28369373, 28915717, 28980058, 28076841, 28818333, 29099487, 28643165, 29190505, 28948977, 29979965, 29702446, 30309854, 30032819, 23630318, 30079495, 30720243, 30630526, 31016814, 30840781, 15722483, 10713666, 9627118, 16861262, 15510160, 12826609, 24641375, 31105275, 33300245, 32994724, 32817165, 33087929, 30224644) (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Jun 05, 2023)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Li-Fraumeni syndrome |
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697444.2
First in ClinVar: Dec 26, 2017 Last updated: Jul 29, 2023 |
Comment:
show
Variant summary: TP53 c.659A>G (p.Tyr220Cys) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251408 control chromosomes (gnomAD). c.659A>G has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome (e.g. Portwine_2000, Iwaza_2008, Lin_2009, Debelenko_2010, Plon_2011, Wang_2013) and in at least three LFS families where the variant co-segregated with disease in affected members genotyped over two-generations (Birch_1994/Varley_1997, Huusko_1999, Lin_2009). This variant has also been reported in early-onset breast cancer patients (Wilson_2010, Melhem-Bertrandt_2012). These data indicate that the variant is very likely to be associated with disease. Functional studies show that the variant severely compromises the p53 binding and transactivation (e.g. Zachos_1998, Kato_2003, Jordan_2010). The following publications have been ascertained in the context of this evaluation (PMID: 8118819, 20028212, 24702488, 10432928, 18307025, 17015838, 20407015, 19101993, 21761402, 21356188, 10922393, 9242456, 23484829, 20805372, 9662334, 12826609). Fifteen submitters, including an expert panel (ClinGen TP53 Variant Curation Expert Panel), have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=13)/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Sep 03, 2023)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Adrenocortical carcinoma, hereditary |
Baylor Genetics
Accession: SCV004206238.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(Nov 14, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome |
Ambry Genetics
Accession: SCV000183774.10
First in ClinVar: Aug 06, 2014 Last updated: Jan 13, 2025 |
Comment:
show
The p.Y220C pathogenic mutation (also known as c.659A>G), located in coding exon 5 of the TP53 gene, results from an A to G substitution at nucleotide position 659. The tyrosine at codon 220 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been reported in several families with classic Li-Fraumeni syndrome (LFS) (Birch et al. Cancer Res.1994 Mar 1;54(5):1298-304; Melham-Bertrand et al. Cancer. 2012 Feb 15;118(4):908-13; Andrade RC et al. Fam Cancer. 2017 04;16:243-248). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). Two other alterations at the same codon, p.Y220H (c.658T>C) and p.Y220N (c.658T>A), are both anticipated to result in a decrease in structural stability (Cho Y, Science 1994 Jul; 265(5170):346-55; Ambry internal data). These variants also were deficient at growth suppression and had a dominant negative effect in multiple functional studies (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). The p.Y220C variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Feb 04, 2025)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Li-Fraumeni syndrome |
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Accession: SCV005689591.2
First in ClinVar: Feb 16, 2025 Last updated: Mar 29, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Squamous cell carcinoma of the head and neck |
Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo
Accession: SCV001450489.2
First in ClinVar: Dec 12, 2020 Last updated: Apr 13, 2025 |
Observation 1
Collection method: case-control
Allele origin: somatic
Affected status: yes
Age: 50-59 years
Sex: male
Geographic origin: Sri Lanka
|
|
|
Pathogenic
(Apr 02, 2020)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Li-Fraumeni syndrome 1 |
Department of Molecular Diagnostics, Institute of Oncology Ljubljana
Accession: SCV001499818.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Dec 23, 2021)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome |
Sema4, Sema4
Accession: SCV002532699.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The TP53 c.659A>G (p.Y220C) variant has been reported in heterozygosity in at least 5 individuals with Li-Fraumeni syndrome, including at least 1 de novo occurrence … (more)
The TP53 c.659A>G (p.Y220C) variant has been reported in heterozygosity in at least 5 individuals with Li-Fraumeni syndrome, including at least 1 de novo occurrence (PMID: 8118819, 10432928, 19101993, 18307025, 10589545). Functional studies indicate that this variant impairs transactivation capacities in yeast and mammalian cells (PMID: 12826609, 15037740, 20407015). This variant was identified in at least three families, where it was found to segregate with the phenotype across 8 meioses/individuals (PMID: 8118819, 10432928, 19101993). This variant was observed in 2/113716 chromosomes in the Non-Finnish European subpopulation in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 127819). Based on the current evidence available, this variant is interpreted as pathogenic. (less)
|
Observation: 1
Collection method: curation
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: curation
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Jul 02, 2018)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Li-Fraumeni syndrome |
Mendelics
Accession: SCV000839116.2
First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(Jan 30, 2023)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
TP53-related condition
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004109437.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
show
The TP53 c.659A>G variant is predicted to result in the amino acid substitution p.Tyr220Cys. This variant has been reported in individuals with Li-Fraumeni syndrome, breast cancer, osteosarcoma and adrenal carcinoma (Birch et al. 1994. PubMed ID: 8118819; Varley et al. 1997. PubMed ID: 9242456; Wilson et al. 2010. PubMed ID: 20805372; Melhem-Bertrandt et al. 2011. PubMed ID: 21761402). Functional study showed that this variant impairs transactivation capacities in yeast and mammalian cells (Jordan et al. 2010. PubMed ID: 20407015). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-7578190-T-C). This variant is interpreted as likely pathogenic/pathogenic by multiple laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127819/). This variant is interpreted as pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Dec 11, 2019)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Li-Fraumeni syndrome
(Autosomal dominant inheritance)
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847987.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
show
The p.Tyr220Cys variant in TP53 has been previously reported in at least 7 individuals with Li-Fraumeni syndrome associated tumors and segregated with disease in at least 10 affected family members (Birch 1994, Huusko 1999, Monti 2007, Lin 2009, Fostira 2015). It has also been identified in 0.002% (2/113716) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that the p.Tyr220Cys variant may impact protein function (Monti 2011); however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analysis suggest that the p.Tyr220Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets our criteria to be classified as pathogenic for Li-Fraumeni syndrome in an autosomal dominant manner. ACMG/AMP Criteria applied: PP1_Strong, PM2, PS3_Moderate, PS4_Moderate, PP3. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Mar 15, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Li-Fraumeni syndrome 1 |
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV005402345.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
show
The TP53 c.659A>G (p.Tyr220Cys) missense change has a maximum subpopulation frequency of 0.002% in gnomAD v2.1.1 (http://gnomad.broadinstitute.org). This variant has been reported in individuals with LFS-associated cancers (PMID: 8118819, 10432928, 10589545, 18307025, 19101993, 20028212, 20805372, 21761402, 24702488, 27714481, 28091804, internal data). Computational evidence supports a deleterious effect of this variant on protein function (Align GVGD = C65, BayesDel = 0.5625). Transactivation assays show a low functioning allele according to Kato et al., and evidence of loss of function and a dominant negative effect according to Giacomelli et al. (PMID 12826609, 30224644). This variant is a somatic hotspot variant in tumors according to the Cancer Hotspots database (cancerhotspots.org). In summary, this variant meets criteria to be classified as pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(May 22, 2023)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome
(Autosomal dominant inheritance)
|
Molecular Diagnostics Laboratory, Catalan Institute of Oncology
Accession: SCV005407760.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
show
c.659A>G, located in exon 6 of the TP53 gene, is predicted to result in the substitution of Tyrosine by Cysteine at codon 220, p.(Tyr220Cys). This variant is found in 2/236878 alleles at a frequency of 0.0008% in the gnomAD v2.1.1 database, non-cancer dataset. The SpliceAI algorithm predicts no significant impact on splicing. In-silico tools predict a pathogenic effect of the variant on protein function (aGVGD: C65; BayesDel: 0.56) (PP3_moderate). Transactivation assays show a non-functional allele according to Kato 2003 (PMID: 12826609) and there is evidence of a dominant negative effect and loss of function according to Giacomelli 2018 (PMID: 30224644) (PS3). At least, this variant has been reported in 4 individuals affected with a TP53-related phenotype, which awards 2 points to this variant as per ClinGen SVI Recommendation for LFS/Chompret Criterion (PMID: 8118819, 10432928, 10589545, 19101993) (PS4_moderate). It has been reported in ClinVar (15x as pathogenic, 21x as likely pathogenic), LOVD (2x as pathogenic, 2x NA), CancerHotspots (127 somatic observations, PM1). Based on the currently available information, c.659A>G is classified as a pathogenic variant according to ClinGen-TP53 Guidelines version 1.4. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Platform type: next-gen sequencing
|
|
|
Pathogenic
(Mar 02, 2017)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Eurofins Ntd Llc (ga)
Accession: SCV000700520.3
First in ClinVar: Apr 02, 2018 Last updated: Apr 13, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 2
Zygosity: 2 Single Heterozygotes
Sex: mixed
|
|
|
Pathogenic
(Jan 15, 2020)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Li-Fraumeni syndrome 1 |
Department of Pathology and Laboratory Medicine, Sinai Health System
Accession: SCV005918344.1
First in ClinVar: Apr 28, 2025 Last updated: Apr 28, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Feb 25, 2025)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Revvity Omics, Revvity
Accession: SCV002022390.4
First in ClinVar: Nov 29, 2021 Last updated: Sep 06, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Jan 28, 2026)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Li-Fraumeni syndrome |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000285206.13
First in ClinVar: Jul 01, 2016 Last updated: Feb 15, 2026 |
Comment:
show
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 220 of the TP53 protein (p.Tyr220Cys). This variant is present in population databases (rs121912666, gnomAD 0.002%). This missense change has been observed in individual(s) with Li-Fraumeni syndrome, breast cancer and adrenal carcinoma (PMID: 8118819, 10432928, 18307025, 19101993, 20805372, 21761402). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 127819). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 20128691, 21343334, 22923379, 23630318, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Dec 08, 2025)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome |
Color Diagnostics, LLC DBA Color Health
Accession: SCV001339381.5
First in ClinVar: Jun 22, 2020 Last updated: Feb 15, 2026 |
Comment:
show
This missense variant replaces tyrosine with cysteine at codon 220 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. \\ Experimental functional studies have demonstrated this variant is defective in transcriptional transactivation studies (PMID: 12826609, 21343334, 22822097), and human cell growth suppression and proliferation assays (PMID: 29979965, 30224644). This variant has been reported in individuals affected with classic Li-Fraumeni syndrome and has been shown to segregate with disease in multiple families (PMID: 8118819, 9242456, 10432928, 10589545, 15977174, 18307025, 19101993). This variant has been observed de novo in an individual with Li-Fraumeni syndrome (PMID: 18307025) and has >100 observations as a somatic hotspot variant (cancerhotspots.org). In addition, this variant has been reported in individuals affected with breast cancer (PMID: 21118481), ovarian cancer (PMID: 24065105, 25404506), astrocytoma (PMID: 20593220) and glioblastoma (PMID: 25256166). This variant has been identified in 2/251408 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Platform type: NGS
|
|
|
Pathogenic
(Aug 01, 2025)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247047.37
First in ClinVar: May 12, 2020 Last updated: Apr 25, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 3
|
|
|
Pathogenic
(Mar 19, 2021)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
B-cell chronic lymphocytic leukemia |
University Health Network, Princess Margaret Cancer Centre
Accession: SCV001738485.1
First in ClinVar: Jun 26, 2021 Last updated: Jun 26, 2021
Comment:
Related to chronic lymphoblastic leukemia
|
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Secondary finding: yes
|
|
|
Likely pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Adrenocortical carcinoma |
Key Laboratory of Carcinogenesis and Cancer Invasion, Central South University
Accession: SCV004046840.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Observation: 1
Collection method: clinical testing
Allele origin: somatic
Affected status: no
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: no
|
|
|
Likely pathogenic
(Dec 01, 2018)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Ovarian neoplasm |
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Accession: SCV000924116.1
First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019 |
Observation 1
Collection method: research
Allele origin: somatic
Affected status: yes
Platform type: next-gen sequencing
|
|
|
Pathogenic
(Jul 01, 2021)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Gastric cancer |
Laboratory for Genotyping Development, RIKEN
Accession: SCV002758171.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
Observation: 1
Collection method: research
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: research
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Oct 01, 2024)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
TP53-related disorder
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV005419153.1
First in ClinVar: Dec 07, 2024 Last updated: Dec 07, 2024 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Aug 21, 2021)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Breast carcinoma
(Autosomal dominant inheritance)
|
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences
Accession: SCV001805828.2
First in ClinVar: Aug 27, 2021 Last updated: Apr 13, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Zygosity: 1 Single Heterozygote
Sex: female
|
|
Comment:
Comment:
Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression activity (Kato 2003, Malcikova 2010, Monti 2011, Giacomelli 2018, Kotler 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23365691, 17015838, 22923379, 27470445, 27503952, 28091804, 28679691, 27322648, 29853601, 20407015, 26619011, 24487413, 20128691, 17606709, 24395441, 19367569, 24573247, 21343334, 18307025, 19101993, 8118819, 10432928, 15977174, 20028212, 20805372, 21761402, 23484829, 24702488, 27840695, 27714481, 23315175, 28861920, 29099488, 28369373, 28915717, 28980058, 28076841, 28818333, 29099487, 28643165, 29190505, 28948977, 29979965, 29702446, 30309854, 30032819, 23630318, 30079495, 30720243, 30630526, 31016814, 30840781, 15722483, 10713666, 9627118, 16861262, 15510160, 12826609, 24641375, 31105275, 33300245, 32994724, 32817165, 33087929, 30224644)
Comment:
Variant summary: TP53 c.659A>G (p.Tyr220Cys) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251408 control chromosomes (gnomAD). c.659A>G has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome (e.g. Portwine_2000, Iwaza_2008, Lin_2009, Debelenko_2010, Plon_2011, Wang_2013) and in at least three LFS families where the variant co-segregated with disease in affected members genotyped over two-generations (Birch_1994/Varley_1997, Huusko_1999, Lin_2009). This variant has also been reported in early-onset breast cancer patients (Wilson_2010, Melhem-Bertrandt_2012). These data indicate that the variant is very likely to be associated with disease. Functional studies show that the variant severely compromises the p53 binding and transactivation (e.g. Zachos_1998, Kato_2003, Jordan_2010). The following publications have been ascertained in the context of this evaluation (PMID: 8118819, 20028212, 24702488, 10432928, 18307025, 17015838, 20407015, 19101993, 21761402, 21356188, 10922393, 9242456, 23484829, 20805372, 9662334, 12826609). Fifteen submitters, including an expert panel (ClinGen TP53 Variant Curation Expert Panel), have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=13)/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The p.Y220C pathogenic mutation (also known as c.659A>G), located in coding exon 5 of the TP53 gene, results from an A to G substitution at nucleotide position 659. The tyrosine at codon 220 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been reported in several families with classic Li-Fraumeni syndrome (LFS) (Birch et al. Cancer Res.1994 Mar 1;54(5):1298-304; Melham-Bertrand et al. Cancer. 2012 Feb 15;118(4):908-13; Andrade RC et al. Fam Cancer. 2017 04;16:243-248). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). Two other alterations at the same codon, p.Y220H (c.658T>C) and p.Y220N (c.658T>A), are both anticipated to result in a decrease in structural stability (Cho Y, Science 1994 Jul; 265(5170):346-55; Ambry internal data). These variants also were deficient at growth suppression and had a dominant negative effect in multiple functional studies (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). The p.Y220C variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
PS4; PS2_MOD; PP1_Strong; PM2_SUP; PS3; PM1; PP3_MOD; PP4_MOD
Comment:
The TP53 c.659A>G variant is predicted to result in the amino acid substitution p.Tyr220Cys. This variant has been reported in individuals with Li-Fraumeni syndrome, breast cancer, osteosarcoma and adrenal carcinoma (Birch et al. 1994. PubMed ID: 8118819; Varley et al. 1997. PubMed ID: 9242456; Wilson et al. 2010. PubMed ID: 20805372; Melhem-Bertrandt et al. 2011. PubMed ID: 21761402). Functional study showed that this variant impairs transactivation capacities in yeast and mammalian cells (Jordan et al. 2010. PubMed ID: 20407015). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-7578190-T-C). This variant is interpreted as likely pathogenic/pathogenic by multiple laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127819/). This variant is interpreted as pathogenic.
Comment:
The p.Tyr220Cys variant in TP53 has been previously reported in at least 7 individuals with Li-Fraumeni syndrome associated tumors and segregated with disease in at least 10 affected family members (Birch 1994, Huusko 1999, Monti 2007, Lin 2009, Fostira 2015). It has also been identified in 0.002% (2/113716) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that the p.Tyr220Cys variant may impact protein function (Monti 2011); however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analysis suggest that the p.Tyr220Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets our criteria to be classified as pathogenic for Li-Fraumeni syndrome in an autosomal dominant manner. ACMG/AMP Criteria applied: PP1_Strong, PM2, PS3_Moderate, PS4_Moderate, PP3.
Comment:
The TP53 c.659A>G (p.Tyr220Cys) missense change has a maximum subpopulation frequency of 0.002% in gnomAD v2.1.1 (http://gnomad.broadinstitute.org). This variant has been reported in individuals with LFS-associated cancers (PMID: 8118819, 10432928, 10589545, 18307025, 19101993, 20028212, 20805372, 21761402, 24702488, 27714481, 28091804, internal data). Computational evidence supports a deleterious effect of this variant on protein function (Align GVGD = C65, BayesDel = 0.5625). Transactivation assays show a low functioning allele according to Kato et al., and evidence of loss of function and a dominant negative effect according to Giacomelli et al. (PMID 12826609, 30224644). This variant is a somatic hotspot variant in tumors according to the Cancer Hotspots database (cancerhotspots.org). In summary, this variant meets criteria to be classified as pathogenic.
Comment:
c.659A>G, located in exon 6 of the TP53 gene, is predicted to result in the substitution of Tyrosine by Cysteine at codon 220, p.(Tyr220Cys). This variant is found in 2/236878 alleles at a frequency of 0.0008% in the gnomAD v2.1.1 database, non-cancer dataset. The SpliceAI algorithm predicts no significant impact on splicing. In-silico tools predict a pathogenic effect of the variant on protein function (aGVGD: C65; BayesDel: 0.56) (PP3_moderate). Transactivation assays show a non-functional allele according to Kato 2003 (PMID: 12826609) and there is evidence of a dominant negative effect and loss of function according to Giacomelli 2018 (PMID: 30224644) (PS3). At least, this variant has been reported in 4 individuals affected with a TP53-related phenotype, which awards 2 points to this variant as per ClinGen SVI Recommendation for LFS/Chompret Criterion (PMID: 8118819, 10432928, 10589545, 19101993) (PS4_moderate). It has been reported in ClinVar (15x as pathogenic, 21x as likely pathogenic), LOVD (2x as pathogenic, 2x NA), CancerHotspots (127 somatic observations, PM1). Based on the currently available information, c.659A>G is classified as a pathogenic variant according to ClinGen-TP53 Guidelines version 1.4.
Comment:
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in Astrocytoma IDH-mutant, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 12826609, 29979965, 30224644). 4) Diagnostic for a specific tumor type/classification according to professional guidelines (Evidence Level A; PMIDs: 33772213, 26061751, 24140581, 21971842, 33692446, 30326163, 37185778).
Comment:
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in ovarian mucinous adenocarcinoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 12826609, 30224644). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 31477716, 26257827, 16322298, 29793804, 23965232).
Comment:
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in colorectal adenocarcinoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 12826609, 30224644). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 22810696, 24078161, 27325016, 28197804, 33924934).
Comment:
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in diffuse midline glioma, H3 K27M-mutant, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 12826609, 30224644). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 24705251, 28966033, 22661320, 34796414, 33433639).
Comment:
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in embryonal rhabdomyosarcoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 12826609, 30224644). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B).
Comment:
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 220 of the TP53 protein (p.Tyr220Cys). This variant is present in population databases (rs121912666, gnomAD 0.002%). This missense change has been observed in individual(s) with Li-Fraumeni syndrome, breast cancer and adrenal carcinoma (PMID: 8118819, 10432928, 18307025, 19101993, 20805372, 21761402). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 127819). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 20128691, 21343334, 22923379, 23630318, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic.
Comment:
This missense variant replaces tyrosine with cysteine at codon 220 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. \\ Experimental functional studies have demonstrated this variant is defective in transcriptional transactivation studies (PMID: 12826609, 21343334, 22822097), and human cell growth suppression and proliferation assays (PMID: 29979965, 30224644). This variant has been reported in individuals affected with classic Li-Fraumeni syndrome and has been shown to segregate with disease in multiple families (PMID: 8118819, 9242456, 10432928, 10589545, 15977174, 18307025, 19101993). This variant has been observed de novo in an individual with Li-Fraumeni syndrome (PMID: 18307025) and has >100 observations as a somatic hotspot variant (cancerhotspots.org). In addition, this variant has been reported in individuals affected with breast cancer (PMID: 21118481), ovarian cancer (PMID: 24065105, 25404506), astrocytoma (PMID: 20593220) and glioblastoma (PMID: 25256166). This variant has been identified in 2/251408 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
TP53: PS3, PM5, PP1:Moderate, PS2:Moderate, PS4:Moderate, PM2:Supporting
Comment:
Invasive Breast Carcinoma grade I EST= + PRO = + HER2 = + KI = 21%
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer. | Usui Y | The New England journal of medicine | 2023 | PMID: 36988593 |
| Specifications of the ACMG/AMP variant interpretation guidelines for germline TP53 variants. | Fortuno C | Human mutation | 2021 | PMID: 33300245 |
| Nucleotide variants and protein expression of TP53 in a Sri Lankan cohort of patients with head and neck cancer. | Manoharan V | Molecular medicine reports | 2019 | PMID: 30816478 |
| The mutational landscape of accelerated- and blast-phase myeloproliferative neoplasms impacts patient outcomes. | McNamara CJ | Blood advances | 2018 | PMID: 30327374 |
| Mutational processes shape the landscape of TP53 mutations in human cancer. | Giacomelli AO | Nature genetics | 2018 | PMID: 30224644 |
| A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation. | Kotler E | Molecular cell | 2018 | PMID: 29979965 |
| Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. | Döhner H | Blood | 2017 | PMID: 27895058 |
| TP53 and CDKN1A mutation analysis in families with Li-Fraumeni and Li-Fraumeni like syndromes. | Andrade RC | Familial cancer | 2017 | PMID: 27714481 |
| The impact of TP53 mutations and TP53 deletions on survival varies between AML, ALL, MDS and CLL: an analysis of 3307 cases. | Stengel A | Leukemia | 2017 | PMID: 27680515 |
| TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. | Welch JS | The New England journal of medicine | 2016 | PMID: 27959731 |
| TP53 mutations in newly diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes. | Kadia TM | Cancer | 2016 | PMID: 27463065 |
| Genomic Classification and Prognosis in Acute Myeloid Leukemia. | Papaemmanuil E | The New England journal of medicine | 2016 | PMID: 27276561 |
| Specific TP53 Mutants Overrepresented in Ovarian Cancer Impact CNV, TP53 Activity, Responses to Nutlin-3a, and Cell Survival. | Mullany LK | Neoplasia (New York, N.Y.) | 2015 | PMID: 26585234 |
| TP53 mutations in de novo acute myeloid leukemia patients: longitudinal follow-ups show the mutation is stable during disease evolution. | Hou HA | Blood cancer journal | 2015 | PMID: 26230955 |
| TP53 mutation characteristics in therapy-related myelodysplastic syndromes and acute myeloid leukemia is similar to de novo diseases. | Ok CY | Journal of hematology & oncology | 2015 | PMID: 25952993 |
| TP53 Y220C Is a Hotspot Mutation in Oropharyngeal Squamous Cell Carcinoma. | van Kempen PM | Pathobiology : journal of immunopathology, molecular and cellular biology | 2015 | PMID: 25765855 |
| Genetic evaluation based on family history and Her2 status correctly identifies TP53 mutations in very early onset breast cancer cases. | Fostira F | Clinical genetics | 2015 | PMID: 24702488 |
| Molecular characterization of serous ovarian carcinoma using a multigene next generation sequencing cancer panel approach. | Ab Mutalib NS | BMC research notes | 2014 | PMID: 25404506 |
| Mutational profiling of kinases in glioblastoma. | Bleeker FE | BMC cancer | 2014 | PMID: 25256166 |
| Heterogeneity of Li-Fraumeni syndrome links to unequal gain-of-function effects of p53 mutations. | Xu J | Scientific reports | 2014 | PMID: 24573247 |
| The consequence of oncomorphic TP53 mutations in ovarian cancer. | Brachova P | International journal of molecular sciences | 2013 | PMID: 24065105 |
| Small molecule induced reactivation of mutant p53 in cancer cells. | Liu X | Nucleic acids research | 2013 | PMID: 23630318 |
| Increased oxidative metabolism in the Li-Fraumeni syndrome. | Wang PY | The New England journal of medicine | 2013 | PMID: 23484829 |
| Functional characterisation of p53 mutants identified in breast cancers with suboptimal responses to anthracyclines or mitomycin. | Berge EO | Biochimica et biophysica acta | 2013 | PMID: 23246812 |
| Rapid profiling of disease alleles using a tunable reporter of protein misfolding. | Pittman AM | Genetics | 2012 | PMID: 22923379 |
| A novel hierarchical prognostic model of AML solely based on molecular mutations. | Grossmann V | Blood | 2012 | PMID: 22915647 |
| The rebel angel: mutant p53 as the driving oncogene in breast cancer. | Walerych D | Carcinogenesis | 2012 | PMID: 22822097 |
| TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. | Rücker FG | Blood | 2012 | PMID: 22186996 |
| Early onset HER2-positive breast cancer is associated with germline TP53 mutations. | Melhem-Bertrandt A | Cancer | 2012 | PMID: 21761402 |
| TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. | Jädersten M | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2011 | PMID: 21519010 |
| Identification of genetic susceptibility to childhood cancer through analysis of genes in parallel. | Plon SE | Cancer genetics | 2011 | PMID: 21356188 |
| Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes. | Monti P | Molecular cancer research : MCR | 2011 | PMID: 21343334 |
| MGMT promoter hypermethylation is a frequent, early, and consistent event in astrocytoma progression, and not correlated with TP53 mutation. | Groenendijk FH | Journal of neuro-oncology | 2011 | PMID: 20593220 |
| BRCA1-mutated and basal-like breast cancers have similar aCGH profiles and a high incidence of protein truncating TP53 mutations. | Holstege H | BMC cancer | 2010 | PMID: 21118481 |
| A novel HER2-positive breast cancer phenotype arising from germline TP53 mutations. | Wilson JR | Journal of medical genetics | 2010 | PMID: 20805372 |
| Altered-function p53 missense mutations identified in breast cancers can have subtle effects on transactivation. | Jordan JJ | Molecular cancer research : MCR | 2010 | PMID: 20407015 |
| Analysis of the DNA-binding activity of p53 mutants using functional protein microarrays and its relationship to transcriptional activation. | Malcikova J | Biological chemistry | 2010 | PMID: 20128691 |
| p53+/mdm2- atypical lipomatous tumor/well-differentiated liposarcoma in young children: an early expression of Li-Fraumeni syndrome. | Debelenko LV | Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society | 2010 | PMID: 20028212 |
| Early detection of adrenocortical carcinoma in a child with Li-Fraumeni syndrome. | Lin MT | Pediatric blood & cancer | 2009 | PMID: 19101993 |
| A Japanese patient with Li-Fraumeni syndrome who had nine primary malignancies associated with a germline mutation of the p53 tumor-suppressor gene. | Izawa N | International journal of clinical oncology | 2008 | PMID: 18307025 |
| Transcriptional functionality of germ line p53 mutants influences cancer phenotype. | Monti P | Clinical cancer research : an official journal of the American Association for Cancer Research | 2007 | PMID: 17606709 |
| Structural basis for understanding oncogenic p53 mutations and designing rescue drugs. | Joerger AC | Proceedings of the National Academy of Sciences of the United States of America | 2006 | PMID: 17015838 |
| Functional analysis and molecular modeling show a preserved wild-type activity of p53(C238Y). | Ferrone M | Molecular cancer therapeutics | 2006 | PMID: 16818505 |
| Evaluation of the molecular mechanisms involved in the gain of function of a Li-Fraumeni TP53 mutation. | Capponcelli S | Human mutation | 2005 | PMID: 15977174 |
| A global suppressor motif for p53 cancer mutants. | Baroni TE | Proceedings of the National Academy of Sciences of the United States of America | 2004 | PMID: 15037740 |
| Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. | Kato S | Proceedings of the National Academy of Sciences of the United States of America | 2003 | PMID: 12826609 |
| A peptide that binds and stabilizes p53 core domain: chaperone strategy for rescue of oncogenic mutants. | Friedler A | Proceedings of the National Academy of Sciences of the United States of America | 2002 | PMID: 11782540 |
| Absence of germline p16(INK4a) alterations in p53 wild type Li-Fraumeni syndrome families. | Portwine C | Journal of medical genetics | 2000 | PMID: 10922393 |
| Germline mutations of p53 but not p16/CDKN2 or PTEN/MMAC1 tumor suppressor genes predispose to gliomas. The ANOCEF Group. Association des NeuroOncologues d'Expression Française. | Zhou XP | Annals of neurology | 1999 | PMID: 10589545 |
| Germ-line TP53 mutations in Finnish cancer families exhibiting features of the Li-Fraumeni syndrome and negative for BRCA1 and BRCA2. | Huusko P | Cancer genetics and cytogenetics | 1999 | PMID: 10432928 |
| Transcriptional regulation of the c-H-ras1 gene by the P53 protein is implicated in the development of human endometrial and ovarian tumours. | Zachos G | Oncogene | 1998 | PMID: 9662334 |
| Germ-line mutations of TP53 in Li-Fraumeni families: an extended study of 39 families. | Varley JM | Cancer research | 1997 | PMID: 9242456 |
| Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families. | Birch JM | Cancer research | 1994 | PMID: 8118819 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TP53 | - | - | - | - |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/4795612b-c5d2-4229-a5ec-172fedfbcf55 | - | - | - | - |
| click to load more citations click to collapse | ||||
Conditions - Somatic
| Tumor type
Help
The tumor type for this variant-condition (RCV) record in ClinVar. |
Clinical impact (# of submissions)
Help
The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Oncogenicity
Help
The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
Variation/condition record
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
|---|---|---|---|---|
|
Oncogenic
criteria provided, single submitter
|
Mar 4, 2025 | RCV004668782.2 | ||
|
Tier I (Strong)
- diagnostic
- supports diagnosis
(1)
|
Oct 7, 2024 | RCV006253805.1 | ||
|
Tier I (Strong)
- diagnostic
- supports diagnosis
(1)
|
Aug 13, 2024 | RCV006253806.1 | ||
|
Tier I (Strong)
- diagnostic
- supports diagnosis
(1)
|
Apr 26, 2024 | RCV006253803.1 | ||
|
Tier I (Strong)
- diagnostic
- supports diagnosis
(1)
|
Nov 18, 2022 | RCV006253802.1 | ||
|
Tier I (Strong)
- diagnostic
- supports diagnosis
(1)
|
Jan 15, 2025 | RCV006253804.1 |
Submissions - Somatic
|
Clinical impact
Help
The submitted somatic clinical impact for each SCV record. (Last evaluated) |
Review Status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Tumor type
Help
The tumor type for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
Expand all rows
Help
This column includes more information supporting the somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|
|
Tier I (Strong)
- Diagnostic
-
supports diagnosis (Apr 26, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Astrocytoma IDH-mutant |
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Accession: SCV007105194.1
First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025 |
Comment:
show
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in Astrocytoma IDH-mutant, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 12826609, 29979965, 30224644). 4) Diagnostic for a specific tumor type/classification according to professional guidelines (Evidence Level A; PMIDs: 33772213, 26061751, 24140581, 21971842, 33692446, 30326163, 37185778). (less)
Observation: 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
|
|
|
Tier I (Strong)
- Diagnostic
-
supports diagnosis (Aug 13, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Ovarian mucinous adenocarcinoma |
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Accession: SCV007105555.1
First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025 |
Comment:
show
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in ovarian mucinous adenocarcinoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 12826609, 30224644). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 31477716, 26257827, 16322298, 29793804, 23965232). (less)
Observation: 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
|
|
|
Tier I (Strong)
- Diagnostic
-
supports diagnosis (Oct 07, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Adenocarcinoma of the large intestine |
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Accession: SCV007105568.1
First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025 |
Comment:
show
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in colorectal adenocarcinoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 12826609, 30224644). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 22810696, 24078161, 27325016, 28197804, 33924934). (less)
Observation: 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
|
|
|
Tier I (Strong)
- Diagnostic
-
supports diagnosis (Jan 15, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Diffuse midline glioma, H3 K27M-mutant |
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Accession: SCV007105582.1
First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025 |
Comment:
show
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in diffuse midline glioma, H3 K27M-mutant, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 12826609, 30224644). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 24705251, 28966033, 22661320, 34796414, 33433639). (less)
Observation: 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
|
|
|
Tier I (Strong)
- Diagnostic
-
supports diagnosis (Nov 18, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Embryonal rhabdomyosarcoma |
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Accession: SCV007104919.1
First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025 |
Comment:
show
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in embryonal rhabdomyosarcoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 12826609, 30224644). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B). (less)
Observation: 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
|
|
|
Oncogenicity
Help
The submitted oncogenicity classification for each SCV record. (Last evaluated) |
Review Status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Tumor type
Help
The tumor type for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
Expand all rows
Help
This column includes more information supporting the somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|
|
Oncogenic
(Mar 04, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Neoplasm |
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV005094428.2
First In ClinVar: Aug 11, 2024 Last updated: Mar 11, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
|
|
Comment:
The NM_000546.6 :c.659A>G variant in TP53 is a missense variant predicted to cause substitution of Tyrosine by Cysteine at amino acid 220 (p.Tyr220Cys). This variant has been reported in 9 unrelated probands and/or families meeting Classic and/or Revised Chompret criteria. Based on this evidence, this variant scores 6.5 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMIDs: 20028212, 9242456, 19101993, 18307025, 20805372, 21761402, 27714481, 10589545, 10432928, 8118819, ClinVar SCV: SCV000183774.8, Internal lab contributors). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 1 individual with an LFS-associated cancer totaling 2 phenotype points (PS2_Moderate; PMID: 18307025). The variant has been reported to segregate with LFS-associated cancers in ≥ 7 meioses from 5 families (PP1_Strong; PMIDs: 20028212, 1910993, 10432928, 8118819, 27714481). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, ClinVar GTRs, SCV000183774.8). This variant has an allele frequency of 0.000005932 (7/1179948 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PMIDs: 12826609, 30224644, 29979965) (PS3). This variant has 127 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (≥ 10 somatic occurrences, PMID: 30311369) (PM1). Computational predictor scores (BayesDel = 0.5625; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4, PS2_Moderate, PP1_Strong, PM2_Supporting, PS3, PM1, PP3_Moderate, PP4_Moderate (Bayesian Points: 21 points; VCEP specifications version 2.0; 7/24/2024)
Comment:
Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression activity (Kato 2003, Malcikova 2010, Monti 2011, Giacomelli 2018, Kotler 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23365691, 17015838, 22923379, 27470445, 27503952, 28091804, 28679691, 27322648, 29853601, 20407015, 26619011, 24487413, 20128691, 17606709, 24395441, 19367569, 24573247, 21343334, 18307025, 19101993, 8118819, 10432928, 15977174, 20028212, 20805372, 21761402, 23484829, 24702488, 27840695, 27714481, 23315175, 28861920, 29099488, 28369373, 28915717, 28980058, 28076841, 28818333, 29099487, 28643165, 29190505, 28948977, 29979965, 29702446, 30309854, 30032819, 23630318, 30079495, 30720243, 30630526, 31016814, 30840781, 15722483, 10713666, 9627118, 16861262, 15510160, 12826609, 24641375, 31105275, 33300245, 32994724, 32817165, 33087929, 30224644)
Comment:
Variant summary: TP53 c.659A>G (p.Tyr220Cys) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251408 control chromosomes (gnomAD). c.659A>G has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome (e.g. Portwine_2000, Iwaza_2008, Lin_2009, Debelenko_2010, Plon_2011, Wang_2013) and in at least three LFS families where the variant co-segregated with disease in affected members genotyped over two-generations (Birch_1994/Varley_1997, Huusko_1999, Lin_2009). This variant has also been reported in early-onset breast cancer patients (Wilson_2010, Melhem-Bertrandt_2012). These data indicate that the variant is very likely to be associated with disease. Functional studies show that the variant severely compromises the p53 binding and transactivation (e.g. Zachos_1998, Kato_2003, Jordan_2010). The following publications have been ascertained in the context of this evaluation (PMID: 8118819, 20028212, 24702488, 10432928, 18307025, 17015838, 20407015, 19101993, 21761402, 21356188, 10922393, 9242456, 23484829, 20805372, 9662334, 12826609). Fifteen submitters, including an expert panel (ClinGen TP53 Variant Curation Expert Panel), have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=13)/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The p.Y220C pathogenic mutation (also known as c.659A>G), located in coding exon 5 of the TP53 gene, results from an A to G substitution at nucleotide position 659. The tyrosine at codon 220 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been reported in several families with classic Li-Fraumeni syndrome (LFS) (Birch et al. Cancer Res.1994 Mar 1;54(5):1298-304; Melham-Bertrand et al. Cancer. 2012 Feb 15;118(4):908-13; Andrade RC et al. Fam Cancer. 2017 04;16:243-248). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). Two other alterations at the same codon, p.Y220H (c.658T>C) and p.Y220N (c.658T>A), are both anticipated to result in a decrease in structural stability (Cho Y, Science 1994 Jul; 265(5170):346-55; Ambry internal data). These variants also were deficient at growth suppression and had a dominant negative effect in multiple functional studies (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). The p.Y220C variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
PS4; PS2_MOD; PP1_Strong; PM2_SUP; PS3; PM1; PP3_MOD; PP4_MOD
Comment:
The TP53 c.659A>G variant is predicted to result in the amino acid substitution p.Tyr220Cys. This variant has been reported in individuals with Li-Fraumeni syndrome, breast cancer, osteosarcoma and adrenal carcinoma (Birch et al. 1994. PubMed ID: 8118819; Varley et al. 1997. PubMed ID: 9242456; Wilson et al. 2010. PubMed ID: 20805372; Melhem-Bertrandt et al. 2011. PubMed ID: 21761402). Functional study showed that this variant impairs transactivation capacities in yeast and mammalian cells (Jordan et al. 2010. PubMed ID: 20407015). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-7578190-T-C). This variant is interpreted as likely pathogenic/pathogenic by multiple laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127819/). This variant is interpreted as pathogenic.
Comment:
The p.Tyr220Cys variant in TP53 has been previously reported in at least 7 individuals with Li-Fraumeni syndrome associated tumors and segregated with disease in at least 10 affected family members (Birch 1994, Huusko 1999, Monti 2007, Lin 2009, Fostira 2015). It has also been identified in 0.002% (2/113716) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that the p.Tyr220Cys variant may impact protein function (Monti 2011); however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analysis suggest that the p.Tyr220Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets our criteria to be classified as pathogenic for Li-Fraumeni syndrome in an autosomal dominant manner. ACMG/AMP Criteria applied: PP1_Strong, PM2, PS3_Moderate, PS4_Moderate, PP3.
Comment:
The TP53 c.659A>G (p.Tyr220Cys) missense change has a maximum subpopulation frequency of 0.002% in gnomAD v2.1.1 (http://gnomad.broadinstitute.org). This variant has been reported in individuals with LFS-associated cancers (PMID: 8118819, 10432928, 10589545, 18307025, 19101993, 20028212, 20805372, 21761402, 24702488, 27714481, 28091804, internal data). Computational evidence supports a deleterious effect of this variant on protein function (Align GVGD = C65, BayesDel = 0.5625). Transactivation assays show a low functioning allele according to Kato et al., and evidence of loss of function and a dominant negative effect according to Giacomelli et al. (PMID 12826609, 30224644). This variant is a somatic hotspot variant in tumors according to the Cancer Hotspots database (cancerhotspots.org). In summary, this variant meets criteria to be classified as pathogenic.
Comment:
c.659A>G, located in exon 6 of the TP53 gene, is predicted to result in the substitution of Tyrosine by Cysteine at codon 220, p.(Tyr220Cys). This variant is found in 2/236878 alleles at a frequency of 0.0008% in the gnomAD v2.1.1 database, non-cancer dataset. The SpliceAI algorithm predicts no significant impact on splicing. In-silico tools predict a pathogenic effect of the variant on protein function (aGVGD: C65; BayesDel: 0.56) (PP3_moderate). Transactivation assays show a non-functional allele according to Kato 2003 (PMID: 12826609) and there is evidence of a dominant negative effect and loss of function according to Giacomelli 2018 (PMID: 30224644) (PS3). At least, this variant has been reported in 4 individuals affected with a TP53-related phenotype, which awards 2 points to this variant as per ClinGen SVI Recommendation for LFS/Chompret Criterion (PMID: 8118819, 10432928, 10589545, 19101993) (PS4_moderate). It has been reported in ClinVar (15x as pathogenic, 21x as likely pathogenic), LOVD (2x as pathogenic, 2x NA), CancerHotspots (127 somatic observations, PM1). Based on the currently available information, c.659A>G is classified as a pathogenic variant according to ClinGen-TP53 Guidelines version 1.4.
Comment:
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in Astrocytoma IDH-mutant, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 12826609, 29979965, 30224644). 4) Diagnostic for a specific tumor type/classification according to professional guidelines (Evidence Level A; PMIDs: 33772213, 26061751, 24140581, 21971842, 33692446, 30326163, 37185778).
Comment:
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in ovarian mucinous adenocarcinoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 12826609, 30224644). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 31477716, 26257827, 16322298, 29793804, 23965232).
Comment:
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in colorectal adenocarcinoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 12826609, 30224644). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 22810696, 24078161, 27325016, 28197804, 33924934).
Comment:
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in diffuse midline glioma, H3 K27M-mutant, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 12826609, 30224644). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 24705251, 28966033, 22661320, 34796414, 33433639).
Comment:
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in embryonal rhabdomyosarcoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 12826609, 30224644). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B).
Comment:
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 220 of the TP53 protein (p.Tyr220Cys). This variant is present in population databases (rs121912666, gnomAD 0.002%). This missense change has been observed in individual(s) with Li-Fraumeni syndrome, breast cancer and adrenal carcinoma (PMID: 8118819, 10432928, 18307025, 19101993, 20805372, 21761402). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 127819). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 20128691, 21343334, 22923379, 23630318, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic.
Comment:
This missense variant replaces tyrosine with cysteine at codon 220 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. \\ Experimental functional studies have demonstrated this variant is defective in transcriptional transactivation studies (PMID: 12826609, 21343334, 22822097), and human cell growth suppression and proliferation assays (PMID: 29979965, 30224644). This variant has been reported in individuals affected with classic Li-Fraumeni syndrome and has been shown to segregate with disease in multiple families (PMID: 8118819, 9242456, 10432928, 10589545, 15977174, 18307025, 19101993). This variant has been observed de novo in an individual with Li-Fraumeni syndrome (PMID: 18307025) and has >100 observations as a somatic hotspot variant (cancerhotspots.org). In addition, this variant has been reported in individuals affected with breast cancer (PMID: 21118481), ovarian cancer (PMID: 24065105, 25404506), astrocytoma (PMID: 20593220) and glioblastoma (PMID: 25256166). This variant has been identified in 2/251408 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
TP53: PS3, PM5, PP1:Moderate, PS2:Moderate, PS4:Moderate, PM2:Supporting
Comment:
Invasive Breast Carcinoma grade I EST= + PRO = + HER2 = + KI = 21%
Citations for somatic classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genomic profiles of IDH-mutant gliomas: MYCN-amplified IDH-mutant astrocytoma had the worst prognosis. | Lee K | Scientific reports | 2023 | PMID: 37185778 |
| H3K27M-mutant diffuse midline gliomas should be further molecularly stratified: an integrated analysis of 669 patients. | Vuong HG | Journal of neuro-oncology | 2021 | PMID: 34796414 |
| The Role of p53 Signaling in Colorectal Cancer. | Liebl MC | Cancers | 2021 | PMID: 33924934 |
| IDH-mutant gliomas with additional class-defining molecular events. | Ahrendsen JT | Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | 2021 | PMID: 33772213 |
| Molecular landscape of IDH-mutant primary astrocytoma Grade IV/glioblastomas. | Wong QH | Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | 2021 | PMID: 33692446 |
| Mutations within FGFR1 are associated with superior outcome in a series of 83 diffuse midline gliomas with H3F3A K27M mutations. | Schüller U | Acta neuropathologica | 2021 | PMID: 33433639 |
| The molecular origin and taxonomy of mucinous ovarian carcinoma. | Cheasley D | Nature communications | 2019 | PMID: 31477716 |
| A dominant-negative effect drives selection of TP53 missense mutations in myeloid malignancies. | Boettcher S | Science (New York, N.Y.) | 2019 | PMID: 31395785 |
| Integrated molecular characterization of IDH-mutant glioblastomas. | Korshunov A | Neuropathology and applied neurobiology | 2019 | PMID: 30326163 |
| Mutational processes shape the landscape of TP53 mutations in human cancer. | Giacomelli AO | Nature genetics | 2018 | PMID: 30224644 |
| A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation. | Kotler E | Molecular cell | 2018 | PMID: 29979965 |
| Massively parallel sequencing analysis of mucinous ovarian carcinomas: genomic profiling and differential diagnoses. | Mueller JJ | Gynecologic oncology | 2018 | PMID: 29793804 |
| Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma. | Mackay A | Cancer cell | 2017 | PMID: 28966033 |
| Molecular alterations in colorectal adenomas and intramucosal adenocarcinomas defined by high-density single-nucleotide polymorphism arrays. | Eizuka M | Journal of gastroenterology | 2017 | PMID: 28197804 |
| Molecular pathological classification of colorectal cancer. | Müller MF | Virchows Archiv : an international journal of pathology | 2016 | PMID: 27325016 |
| Mutational landscape of mucinous ovarian carcinoma and its neoplastic precursors. | Ryland GL | Genome medicine | 2015 | PMID: 26257827 |
| Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas. | Cancer Genome Atlas Research Network | The New England journal of medicine | 2015 | PMID: 26061751 |
| The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. | Wu G | Nature genetics | 2014 | PMID: 24705251 |
| The genetic landscape of anaplastic astrocytoma. | Killela PJ | Oncotarget | 2014 | PMID: 24140581 |
| KRAS mutations in colorectal cancer from Tunisia: relationships with clinicopathologic variables and data on TP53 mutations and microsatellite instability. | Aissi S | Molecular biology reports | 2013 | PMID: 24078161 |
| TP53 mutations are common in all subtypes of epithelial ovarian cancer and occur concomitantly with KRAS mutations in the mucinous type. | Rechsteiner M | Experimental and molecular pathology | 2013 | PMID: 23965232 |
| Small molecule induced reactivation of mutant p53 in cancer cells. | Liu X | Nucleic acids research | 2013 | PMID: 23630318 |
| Comprehensive molecular characterization of human colon and rectal cancer. | Cancer Genome Atlas Network | Nature | 2012 | PMID: 22810696 |
| K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. | Khuong-Quang DA | Acta neuropathologica | 2012 | PMID: 22661320 |
| IDH1/2 gene status defines the prognosis and molecular profiles in patients with grade III gliomas. | Shibahara I | International journal of clinical oncology | 2012 | PMID: 21971842 |
| Inactive full-length p53 mutants lacking dominant wild-type p53 inhibition highlight loss of heterozygosity as an important aspect of p53 status in human cancers. | Dearth LR | Carcinogenesis | 2007 | PMID: 16861262 |
| Clinical relevance of dominant-negative p73 isoforms for responsiveness to chemotherapy and survival in ovarian cancer: evidence for a crucial p53-p73 cross-talk in vivo. | Concin N | Clinical cancer research : an official journal of the American Association for Cancer Research | 2005 | PMID: 16322298 |
| Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. | Kato S | Proceedings of the National Academy of Sciences of the United States of America | 2003 | PMID: 12826609 |
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Submissions - Functional Data
functionally abnormal
--
retained intron
assessed by
RNAseq
Result:
junction spanning - intron inclusion with mutation (p=0.0),read abundance - intron inclusion (p=0.0056)
Modifies an exonic cryptic donor site at NC_000017.10:g.7578190 from -16.18 to 2.46 bits. Significant p-values: junction spanning - intron inclusion with mutation (3 reads, p=0.0), read abundance - intron inclusion (29 reads, p=0.0056). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.
Citation:
PubMed: 31275557
Accession: SCV006900306.1
Submitted: 2025-10-17
Assay description:
In the sample (TCGA-BL-A13J), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)
- Disease context: Malignant tumor of urinary bladder
- Transcript, protein change: NM_000546.6:c.659A>G, Y220C
- Molecular phenotype measured: splicing
- Cell line: TCGA-BL-A13J
- Tissue: Bladder Urothelial Carcinoma (BLCA)
- Collection method: in vitro
- Species: human
- Number of controls: 377
functionally abnormal
--
retained intron
assessed by
RNAseq
Result:
junction spanning - intron inclusion with mutation (p=0.0)
Modifies an exonic cryptic donor site at NC_000017.10:g.7578190 from -16.18 to 2.46 bits. Significant p-values: junction spanning - intron inclusion with mutation (6 reads, p=0.0). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.
Citation:
PubMed: 31275557
Accession: SCV006900307.1
Submitted: 2025-10-17
Assay description:
In the sample (TCGA-86-8074), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)
- Disease context: Lung cancer
- Transcript, protein change: NM_000546.6:c.659A>G, Y220C
- Molecular phenotype measured: splicing
- Cell line: TCGA-86-8074
- Tissue: Lung Adenocarcinoma (LUAD)
- Collection method: in vitro
- Species: human
- Number of controls: 599
functionally abnormal
--
retained intron
assessed by
RNAseq
Result:
junction spanning - intron inclusion with mutation (p=0.0)
Modifies an exonic cryptic donor site at NC_000017.10:g.7578190 from -16.18 to 2.46 bits. Significant p-values: junction spanning - intron inclusion with mutation (1 reads, p=0.0). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.
Citation:
PubMed: 31275557
Accession: SCV006900308.1
Submitted: 2025-10-17
Assay description:
In the sample (TCGA-91-6840), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)
- Disease context: Lung cancer
- Transcript, protein change: NM_000546.6:c.659A>G, Y220C
- Molecular phenotype measured: splicing
- Cell line: TCGA-91-6840
- Tissue: Lung Adenocarcinoma (LUAD)
- Collection method: in vitro
- Species: human
- Number of controls: 599
functionally abnormal
--
retained intron
assessed by
RNAseq
Result:
junction spanning - intron inclusion with mutation (p=0.0)
Modifies an exonic cryptic donor site at NC_000017.10:g.7578190 from -16.18 to 2.46 bits. Significant p-values: junction spanning - intron inclusion with mutation (4 reads, p=0.0). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.
Citation:
PubMed: 31275557
Accession: SCV006900309.1
Submitted: 2025-10-17
Assay description:
In the sample (TCGA-B6-A0IJ), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)
- Disease context: Familial cancer of breast
- Transcript, protein change: NM_000546.6:c.659A>G, Y220C
- Molecular phenotype measured: splicing
- Cell line: TCGA-B6-A0IJ
- Tissue: Breast Invasive Carcinoma (BRCA)
- Collection method: in vitro
- Species: human
- Number of controls: 547
functionally abnormal
--
retained intron
assessed by
RNAseq
Result:
junction spanning - intron inclusion with mutation (p=0.0)
Modifies an exonic cryptic donor site at NC_000017.10:g.7578190 from -16.18 to 2.46 bits. Significant p-values: junction spanning - intron inclusion with mutation (1 reads, p=0.0). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.
Citation:
PubMed: 31275557
Accession: SCV006900310.1
Submitted: 2025-10-17
Assay description:
In the sample (TCGA-A1-A0SO), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)
- Disease context: Familial cancer of breast
- Transcript, protein change: NM_000546.6:c.659A>G, Y220C
- Molecular phenotype measured: splicing
- Cell line: TCGA-A1-A0SO
- Tissue: Breast Invasive Carcinoma (BRCA)
- Collection method: in vitro
- Species: human
- Number of controls: 547
functionally abnormal
--
retained intron
assessed by
RNAseq
Result:
junction spanning - intron inclusion with mutation (p=0.0)
Modifies an exonic cryptic donor site at NC_000017.10:g.7578190 from -16.18 to 2.46 bits. Significant p-values: junction spanning - intron inclusion with mutation (1 reads, p=0.0). ; Modifies an exonic cryptic donor site at NC_000017.10:g.7578190 from -16.18 to 2.46 bits. Significant p-values: junction spanning - intron inclusion with mutation (1 reads, p=0.0). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.
Citation:
PubMed: 31275557
Accession: SCV006900311.1
Submitted: 2025-10-17
Assay description:
In the sample (TCGA-E2-A573), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)
- Disease context: Familial cancer of breast
- Transcript, protein change: NM_000546.6:c.659A>G, Y220C
- Molecular phenotype measured: splicing
- Cell line: TCGA-E2-A573
- Tissue: Breast Invasive Carcinoma (BRCA)
- Collection method: in vitro
- Species: human
- Number of controls: 473
functionally abnormal
--
retained intron
assessed by
RNAseq
Result:
junction spanning - intron inclusion with mutation (p=0.0)
Modifies an exonic cryptic donor site at NC_000017.10:g.7578190 from -16.18 to 2.46 bits. Significant p-values: junction spanning - intron inclusion with mutation (3 reads, p=0.0). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.
Citation:
PubMed: 31275557
Accession: SCV006900312.1
Submitted: 2025-10-17
Assay description:
In the sample (TCGA-E9-A1ND), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)
- Disease context: Familial cancer of breast
- Transcript, protein change: NM_000546.6:c.659A>G, Y220C
- Molecular phenotype measured: splicing
- Cell line: TCGA-E9-A1ND
- Tissue: Breast Invasive Carcinoma (BRCA)
- Collection method: in vitro
- Species: human
- Number of controls: 615
functionally abnormal
--
retained intron
assessed by
RNAseq
Result:
junction spanning - intron inclusion (p=0.0376),junction spanning - intron inclusion with mutation (p=0.0),read abundance - intron inclusion (p=0.0008)
Modifies an exonic cryptic donor site at NC_000017.10:g.7578190 from -16.18 to 2.46 bits. Significant p-values: junction spanning - intron inclusion (24 reads, p=0.0376), junction spanning - intron inclusion with mutation (21 reads, p=0.0), read abundance - intron inclusion (35 reads, p=0.0008). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.
Citation:
PubMed: 31275557
Accession: SCV006900314.1
Submitted: 2025-10-17
Assay description:
In the sample (TCGA-QK-A6VB), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)
- Disease context: Squamous cell carcinoma of the head and neck
- Transcript, protein change: NM_000546.6:c.659A>G, Y220C
- Molecular phenotype measured: splicing
- Cell line: TCGA-QK-A6VB
- Tissue: Head and Neck Squamous Cell Carcinoma (HNSC)
- Collection method: in vitro
- Species: human
- Number of controls: 521
functionally abnormal
--
retained intron
assessed by
RNAseq
Result:
junction spanning - intron inclusion with mutation (p=0.0)
Modifies an exonic cryptic donor site at NC_000017.10:g.7578190 from -16.18 to 2.46 bits. Significant p-values: junction spanning - intron inclusion with mutation (9 reads, p=0.0). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.
Citation:
PubMed: 31275557
Accession: SCV006900315.1
Submitted: 2025-10-17
Assay description:
In the sample (TCGA-CV-7435), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)
- Disease context: Squamous cell carcinoma of the head and neck
- Transcript, protein change: NM_000546.6:c.659A>G, Y220C
- Molecular phenotype measured: splicing
- Cell line: TCGA-CV-7435
- Tissue: Head and Neck Squamous Cell Carcinoma (HNSC)
- Collection method: in vitro
- Species: human
- Number of controls: 521
functionally abnormal
--
retained intron
assessed by
RNAseq
Result:
junction spanning - intron inclusion with mutation (p=0.0)
Modifies an exonic cryptic donor site at NC_000017.10:g.7578190 from -16.18 to 2.46 bits. Significant p-values: junction spanning - intron inclusion with mutation (3 reads, p=0.0). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.
Citation:
PubMed: 31275557
Accession: SCV006900316.1
Submitted: 2025-10-17
Assay description:
In the sample (TCGA-P3-A6T8), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)
- Disease context: Squamous cell carcinoma of the head and neck
- Transcript, protein change: NM_000546.6:c.659A>G, Y220C
- Molecular phenotype measured: splicing
- Cell line: TCGA-P3-A6T8
- Tissue: Head and Neck Squamous Cell Carcinoma (HNSC)
- Collection method: in vitro
- Species: human
- Number of controls: 521
functionally abnormal
--
retained intron
assessed by
RNAseq
Result:
junction spanning - intron inclusion with mutation (p=0.0)
Modifies an exonic cryptic donor site at NC_000017.10:g.7578190 from -16.18 to 2.46 bits. Significant p-values: junction spanning - intron inclusion with mutation (17 reads, p=0.0). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.
Citation:
PubMed: 31275557
Accession: SCV006900317.1
Submitted: 2025-10-17
Assay description:
In the sample (TCGA-QK-AA3J), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)
- Disease context: Squamous cell carcinoma of the head and neck
- Transcript, protein change: NM_000546.6:c.659A>G, Y220C
- Molecular phenotype measured: splicing
- Cell line: TCGA-QK-AA3J
- Tissue: Head and Neck Squamous Cell Carcinoma (HNSC)
- Collection method: in vitro
- Species: human
- Number of controls: 521
functionally abnormal
--
retained intron
assessed by
RNAseq
Result:
junction spanning - intron inclusion with mutation (p=0.0)
Modifies an exonic cryptic donor site at NC_000017.10:g.7578190 from -16.18 to 2.46 bits. Significant p-values: junction spanning - intron inclusion with mutation (1 reads, p=0.0). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.
Citation:
PubMed: 31275557
Accession: SCV006900318.1
Submitted: 2025-10-17
Assay description:
In the sample (TCGA-CV-A45W), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)
- Disease context: Squamous cell carcinoma of the head and neck
- Transcript, protein change: NM_000546.6:c.659A>G, Y220C
- Molecular phenotype measured: splicing
- Cell line: TCGA-CV-A45W
- Tissue: Head and Neck Squamous Cell Carcinoma (HNSC)
- Collection method: in vitro
- Species: human
- Number of controls: 521
functionally abnormal
--
retained intron
assessed by
RNAseq
Result:
junction spanning - intron inclusion with mutation (p=0.0)
Modifies an exonic cryptic donor site at NC_000017.10:g.7578190 from -16.18 to 2.46 bits. Significant p-values: junction spanning - intron inclusion with mutation (7 reads, p=0.0). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.
Citation:
PubMed: 31275557
Accession: SCV006900319.1
Submitted: 2025-10-17
Assay description:
In the sample (TCGA-CV-5976), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)
- Disease context: Squamous cell carcinoma of the head and neck
- Transcript, protein change: NM_000546.6:c.659A>G, Y220C
- Molecular phenotype measured: splicing
- Cell line: TCGA-CV-5976
- Tissue: Head and Neck Squamous Cell Carcinoma (HNSC)
- Collection method: in vitro
- Species: human
- Number of controls: 521
functionally abnormal
--
retained intron
assessed by
RNAseq
Result:
junction spanning - intron inclusion with mutation (p=0.0)
Modifies an exonic cryptic donor site at NC_000017.10:g.7578190 from -16.18 to 2.46 bits. Significant p-values: junction spanning - intron inclusion with mutation (2 reads, p=0.0). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.
Citation:
PubMed: 31275557
Accession: SCV006900320.1
Submitted: 2025-10-17
Assay description:
In the sample (TCGA-G4-6625), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)
- Disease context: Colon adenocarcinoma
- Transcript, protein change: NM_000546.6:c.659A>G, Y220C
- Molecular phenotype measured: splicing
- Cell line: TCGA-G4-6625
- Tissue: Colon Adenocarcinoma (COAD)
- Collection method: in vitro
- Species: human
- Number of controls: 315
functionally abnormal
--
retained intron
assessed by
RNAseq
Result:
junction spanning - intron inclusion with mutation (p=0.0)
Modifies an exonic cryptic donor site at NC_000017.10:g.7578190 from -16.18 to 2.46 bits. Significant p-values: junction spanning - intron inclusion with mutation (1 reads, p=0.0). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.
Citation:
PubMed: 31275557
Accession: SCV006900321.1
Submitted: 2025-10-17
Assay description:
In the sample (TCGA-DM-A28F), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)
- Disease context: Colon adenocarcinoma
- Transcript, protein change: NM_000546.6:c.659A>G, Y220C
- Molecular phenotype measured: splicing
- Cell line: TCGA-DM-A28F
- Tissue: Colon Adenocarcinoma (COAD)
- Collection method: in vitro
- Species: human
- Number of controls: 315
functionally abnormal
--
retained intron
assessed by
RNAseq
Result:
junction spanning - intron inclusion with mutation (p=0.0)
Modifies an exonic cryptic donor site at NC_000017.10:g.7578190 from -16.18 to 2.46 bits. Significant p-values: junction spanning - intron inclusion with mutation (7 reads, p=0.0). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.
Citation:
PubMed: 31275557
Accession: SCV006900322.1
Submitted: 2025-10-17
Assay description:
In the sample (TCGA-85-6798), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)
- Disease context: Squamous cell lung carcinoma
- Transcript, protein change: NM_000546.6:c.659A>G, Y220C
- Molecular phenotype measured: splicing
- Cell line: TCGA-85-6798
- Tissue: Lung Squamous Cell Carcinoma (LUSC)
- Collection method: in vitro
- Species: human
- Number of controls: 329
functionally abnormal
--
retained intron
assessed by
RNAseq
Result:
junction spanning - intron inclusion with mutation (p=0.0)
Modifies an exonic cryptic donor site at NC_000017.10:g.7578190 from -16.18 to 2.46 bits. Significant p-values: junction spanning - intron inclusion with mutation (1 reads, p=0.0). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.
Citation:
PubMed: 31275557
Accession: SCV006900323.1
Submitted: 2025-10-17
Assay description:
In the sample (TCGA-PC-A5DK), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)
- Disease context: Sarcoma
- Transcript, protein change: NM_000546.6:c.659A>G, Y220C
- Molecular phenotype measured: splicing
- Cell line: TCGA-PC-A5DK
- Tissue: Sarcoma (SARC)
- Collection method: in vitro
- Species: human
- Number of controls: 255
functionally abnormal
--
retained intron
assessed by
RNAseq
Result:
junction spanning - intron inclusion with mutation (p=0.0)
Modifies an exonic cryptic donor site at NC_000017.10:g.7578190 from -16.18 to 2.46 bits. Significant p-values: junction spanning - intron inclusion with mutation (1 reads, p=0.0). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.
Citation:
PubMed: 31275557
Accession: SCV006900326.1
Submitted: 2025-10-17
Assay description:
In the sample (TCGA-F2-6879), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)
- Disease context: Pancreatic adenocarcinoma
- Transcript, protein change: NM_000546.6:c.659A>G, Y220C
- Molecular phenotype measured: splicing
- Cell line: TCGA-F2-6879
- Tissue: Pancreatic Adenocarcinoma (PAAD)
- Collection method: in vitro
- Species: human
- Number of controls: 179
functionally abnormal
--
retained intron
assessed by
RNAseq
Result:
junction spanning - intron inclusion with mutation (p=0.0)
Modifies an exonic cryptic donor site at NC_000017.10:g.7578190 from -16.18 to 2.46 bits. Significant p-values: junction spanning - intron inclusion with mutation (4 reads, p=0.0). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.
Citation:
PubMed: 31275557
Accession: SCV006900327.1
Submitted: 2025-10-17
Assay description:
In the sample (TCGA-06-0644), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)
- Disease context: Glioma susceptibility 1
- Transcript, protein change: NM_000546.6:c.659A>G, Y220C
- Molecular phenotype measured: splicing
- Cell line: TCGA-06-0644
- Tissue: Glioblastoma Multiforme (GBM)
- Collection method: in vitro
- Species: human
- Number of controls: 171
functionally abnormal
--
retained intron
assessed by
RNAseq
Result:
junction spanning - intron inclusion with mutation (p=0.0)
Modifies an exonic cryptic donor site at NC_000017.10:g.7578190 from -16.18 to 2.46 bits. Significant p-values: junction spanning - intron inclusion with mutation (6 reads, p=0.0). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.
Citation:
PubMed: 31275557
Accession: SCV006900328.1
Submitted: 2025-10-17
Assay description:
In the sample (TCGA-VQ-AA6A), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)
- Disease context: Gastric cancer
- Transcript, protein change: NM_000546.6:c.659A>G, Y220C
- Molecular phenotype measured: splicing
- Cell line: TCGA-VQ-AA6A
- Tissue: Stomach Adenocarcinoma (STAD)
- Collection method: in vitro
- Species: human
- Number of controls: 656
functionally abnormal
--
retained intron
assessed by
RNAseq
Result:
junction spanning - intron inclusion with mutation (p=0.0)
Modifies an exonic cryptic donor site at NC_000017.10:g.7578190 from -16.18 to 2.46 bits. Significant p-values: junction spanning - intron inclusion with mutation (2 reads, p=0.0). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.
Citation:
PubMed: 31275557
Accession: SCV006900329.1
Submitted: 2025-10-17
Assay description:
In the sample (TCGA-VQ-AA6G), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)
- Disease context: Gastric cancer
- Transcript, protein change: NM_000546.6:c.659A>G, Y220C
- Molecular phenotype measured: splicing
- Cell line: TCGA-VQ-AA6G
- Tissue: Stomach Adenocarcinoma (STAD)
- Collection method: in vitro
- Species: human
- Number of controls: 656
functionally abnormal
--
retained intron
assessed by
RNAseq
Result:
junction spanning - intron inclusion with mutation (p=0.0)
Modifies an exonic cryptic donor site at NC_000017.10:g.7578190 from -16.18 to 2.46 bits. Significant p-values: junction spanning - intron inclusion with mutation (11 reads, p=0.0). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.
Citation:
PubMed: 31275557
Accession: SCV006900330.1
Submitted: 2025-10-17
Assay description:
In the sample (TCGA-L5-A43J), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)
- Disease context: Malignant tumor of esophagus
- Transcript, protein change: NM_000546.6:c.659A>G, Y220C
- Molecular phenotype measured: splicing
- Cell line: TCGA-L5-A43J
- Tissue: Esophageal Carcinoma (ESCA)
- Collection method: in vitro
- Species: human
- Number of controls: 282
functionally abnormal
--
retained intron
assessed by
RNAseq
Result:
junction spanning - intron inclusion with mutation (p=0.0)
Modifies an exonic cryptic donor site at NC_000017.10:g.7578190 from -16.18 to 2.46 bits. Significant p-values: junction spanning - intron inclusion with mutation (16 reads, p=0.0). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.
Citation:
PubMed: 31275557
Accession: SCV006900331.1
Submitted: 2025-10-17
Assay description:
In the sample (TCGA-L5-A88V), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)
- Disease context: Malignant tumor of esophagus
- Transcript, protein change: NM_000546.6:c.659A>G, Y220C
- Molecular phenotype measured: splicing
- Cell line: TCGA-L5-A88V
- Tissue: Esophageal Carcinoma (ESCA)
- Collection method: in vitro
- Species: human
- Number of controls: 282
functionally abnormal
--
retained intron
assessed by
RNAseq
Result:
junction spanning - intron inclusion with mutation (p=0.0)
Modifies an exonic cryptic donor site at NC_000017.10:g.7578190 from -16.18 to 2.46 bits. Significant p-values: junction spanning - intron inclusion with mutation (4 reads, p=0.0). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.
Citation:
PubMed: 31275557
Accession: SCV006900332.1
Submitted: 2025-10-17
Assay description:
In the sample (TCGA-IG-A5B8), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)
- Disease context: Malignant tumor of esophagus
- Transcript, protein change: NM_000546.6:c.659A>G, Y220C
- Molecular phenotype measured: splicing
- Cell line: TCGA-IG-A5B8
- Tissue: Esophageal Carcinoma (ESCA)
- Collection method: in vitro
- Species: human
- Number of controls: 282
functionally abnormal
--
retained intron
assessed by
RNAseq
Result:
junction spanning - intron inclusion with mutation (p=0.0)
Modifies an exonic cryptic donor site at NC_000017.10:g.7578190 from -16.18 to 2.46 bits. Significant p-values: junction spanning - intron inclusion with mutation (5 reads, p=0.0). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.
Citation:
PubMed: 31275557
Accession: SCV006900333.1
Submitted: 2025-10-17
Assay description:
In the sample (TCGA-LN-A49S), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)
- Disease context: Malignant tumor of esophagus
- Transcript, protein change: NM_000546.6:c.659A>G, Y220C
- Molecular phenotype measured: splicing
- Cell line: TCGA-LN-A49S
- Tissue: Esophageal Carcinoma (ESCA)
- Collection method: in vitro
- Species: human
- Number of controls: 282
Text-mined citations for rs121912666 ...
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Record last updated Apr 26, 2026
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.