VCV000127819.93 - ClinVar

NM_000546.6(TP53):c.659A>G (p.Tyr220Cys)

Germline

Reviewed by expert panel

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

The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

FDA Recognized Database

Somatic

No data submitted for somatic clinical impact

Somatic

Oncogenicity

criteria provided, single submitter. Learn more about how ClinVar calculates review status.

Oncogenic

This classification is based on the single submission received

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.

Variant Details

Identifiers

NM_000546.6(TP53):c.659A>G (p.Tyr220Cys)

Variation ID: 127819 Accession: VCV000127819.93

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	May 25, 2025	Aug 5, 2024
Somatic - Oncogenicity	Aug 11, 2024	Mar 11, 2025	Mar 4, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_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

... more HGVS ... less HGVS

Protein change

Y181C, Y220C, Y88C, Y61C

Other names

p.Y220C:TAT>TGT
NM_000546.6(TP53):c.659A>G

Canonical SPDI

NC_000017.11:7674871:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Trans-Omics for Precision Medicine (TOPMed) 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Exome Aggregation Consortium (ExAC) 0.00003

Links

ClinGen: CA000315 UniProtKB: P04637#VAR_005957 dbSNP: rs121912666 VarSome

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
Gene	OMIM	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	3580	3681

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.
Hereditary cancer-predisposing syndrome	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Nov 14, 2024	RCV000115731.19
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Oct 1, 2024	RCV000213055.45
Li-Fraumeni syndrome	Pathogenic (6)	reviewed by expert panel	Aug 5, 2024	RCV000232050.22
Squamous cell carcinoma of the head and neck	Pathogenic (1)	criteria provided, single submitter	-	RCV000433936.6
Ovarian neoplasm	Likely pathogenic (1)	no assertion criteria provided	Dec 1, 2018	RCV000785544.4
B-cell chronic lymphocytic leukemia	Pathogenic (1)	no assertion criteria provided	Mar 19, 2021	RCV001527468.4
Li-Fraumeni syndrome 1	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Mar 15, 2024	RCV001310212.5
Breast carcinoma	Pathogenic (1)	no assertion criteria provided	Aug 21, 2021	RCV001579295.4
Adrenocortical carcinoma, hereditary Basal cell carcinoma, susceptibility to, 7 Bone marrow failure syndrome 5 Bone osteosarcoma Carcinoma of pancreas Choroid plexus papilloma Colorectal cancer Familial cancer of breast Glioma susceptibility 1 Hepatocellular carcinoma Li-Fraumeni syndrome 1 Nasopharyngeal carcinoma	Pathogenic (1)	criteria provided, single submitter	Apr 10, 2022	RCV002490776.2
Gastric cancer	Pathogenic (1)	no assertion criteria provided	Jul 1, 2021	RCV003162539.2
TP53-related disorder	Pathogenic (2)	criteria provided, single submitter	Jan 30, 2023	RCV003407499.5
Adrenocortical carcinoma, hereditary	Pathogenic (1)	criteria provided, single submitter	Sep 3, 2023	RCV003460829.1
Adrenal cortex carcinoma	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.	More information 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.
Pathogenic (Aug 05, 2024) C Contributing to aggregate classification	reviewed by expert panel (ClinGen TP53 ACMG Specifications TP53 V2.0.0) Method: curation	Li-Fraumeni syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	ClinGen TP53 Variant Curation Expert Panel, ClinGen FDA Recognized Database Accession: SCV001142546.2 First in ClinVar: Jan 12, 2020 Last updated: Aug 18, 2024	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/4795612b-c5d2-4229-a5ec-172fedfbcf55 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 … (more) 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)

Pathogenic (Apr 02, 2020) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni syndrome 1 Affected status: yes Allele origin: germline	Department of Molecular Diagnostics, Institute of Oncology Ljubljana Accession: SCV001499818.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021

Pathogenic (Aug 01, 2018) N Not contributing to aggregate classification	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000888669.2 First in ClinVar: Dec 15, 2018 Last updated: Jan 01, 2022

Pathogenic (Apr 10, 2022) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	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 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002797313.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022

Pathogenic (Jul 27, 2022) N Not contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000149640.17 First in ClinVar: May 17, 2014 Last updated: Mar 04, 2023	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 … (more) 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)

Pathogenic (Jun 05, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Li-Fraumeni syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000697444.2 First in ClinVar: Dec 26, 2017 Last updated: Jul 29, 2023	Publications: PubMed (33) PubMed: 10922393‚ 17606709‚ 21343334‚ 20407015‚ 21761402‚ 12826609‚ 10432928‚ 9242456‚ 21356188‚ 8118819‚ 24702488‚ 17015838‚ 9662334‚ 20805372‚ 23484829‚ 19101993‚ 18307025‚ 20028212‚ 26230955‚ 21519010‚ 27463065‚ 25952993‚ 22186996‚ 27680515‚ 27959731‚ 16818505‚ 27895058‚ 30327374‚ 11782540‚ 23246812‚ 22915647‚ 26585234‚ 27276561 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 … (more) 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)

Pathogenic (Sep 03, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Adrenocortical carcinoma, hereditary Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004206238.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023

Pathogenic (May 10, 2019) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002022390.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024

Pathogenic (Mar 15, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (St. Jude Assertion Criteria 2020) Method: clinical testing	Li-Fraumeni syndrome 1 Affected status: yes Allele origin: germline	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: 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 … (more) 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)

Pathogenic (May 22, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (Fortuno et al. (Hum Mutat. 2021)) Method: clinical testing	Hereditary cancer-predisposing syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Molecular Diagnostics Laboratory, Catalan Institute of Oncology Accession: SCV005407760.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (6) PubMed: 12826609‚ 30224644‚ 8118819‚ 10432928‚ 10589545‚ 19101993 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 … (more) 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)

Pathogenic (Nov 14, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000183774.10 First in ClinVar: Aug 06, 2014 Last updated: Jan 13, 2025	Publications: PubMed (3) PubMed: 21761402‚ 27714481‚ 8118819 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 … (more) 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)

Pathogenic (Feb 04, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni syndrome Affected status: unknown Allele origin: germline	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet Accession: SCV005689591.2 First in ClinVar: Feb 16, 2025 Last updated: Mar 29, 2025	Comment: PS4; PS2_MOD; PP1_Strong; PM2_SUP; PS3; PM1; PP3_MOD; PP4_MOD

Pathogenic (Mar 02, 2017) N Not contributing to aggregate classification	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000700520.3 First in ClinVar: Apr 02, 2018 Last updated: Apr 13, 2025	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TP53 Number of individuals with the variant: 2 Zygosity: Single Heterozygote Sex: mixed

Pathogenic (Jan 15, 2020) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni syndrome 1 Affected status: yes Allele origin: germline	Department of Pathology and Laboratory Medicine, Sinai Health System Accession: SCV005918344.1 First in ClinVar: Apr 28, 2025 Last updated: Apr 28, 2025	Publications: PubMed (9) PubMed: 19101993‚ 8118819‚ 25765855‚ 21761402‚ 20805372‚ 10432928‚ 20128691‚ 21343334‚ 17015838

Pathogenic (Aug 13, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV001339381.4 First in ClinVar: Jun 22, 2020 Last updated: May 03, 2025	Publications: PubMed (17) PubMed: 8118819‚ 9242456‚ 10432928‚ 10589545‚ 12826609‚ 15977174‚ 18307025‚ 19101993‚ 20593220‚ 21118481‚ 21343334‚ 22822097‚ 24065105‚ 25256166‚ 25404506‚ 29979965‚ 30224644 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 … (more) 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 defecting 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)

Pathogenic (Dec 23, 2021) N Not contributing to aggregate classification	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	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)	Publications: PubMed (8) PubMed: 8118819‚ 10432928‚ 19101993‚ 18307025‚ 10589545‚ 12826609‚ 15037740‚ 20407015

Pathogenic (Jul 02, 2018) N Not contributing to aggregate classification	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Li-Fraumeni syndrome Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV000839116.2 First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022

Pathogenic (Jan 30, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	TP53-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004109437.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	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 … (more) 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)

Pathogenic (Dec 11, 2019) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004847987.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Publications: PubMed (8) PubMed: 24573247‚ 21343334‚ 8118819‚ 25765855‚ 19101993‚ 17606709‚ 10432928‚ 24702488 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 … (more) 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)

Pathogenic (Jan 05, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Li-Fraumeni syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000285206.12 First in ClinVar: Jul 01, 2016 Last updated: Feb 25, 2025	Publications: PubMed (14) PubMed: 28492532‚ 8118819‚ 10432928‚ 18307025‚ 19101993‚ 20805372‚ 21761402‚ 12826609‚ 29979965‚ 30224644‚ 20128691‚ 21343334‚ 22923379‚ 23630318 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 … (more) 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)

Pathogenic (-) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: case-control	Squamous cell carcinoma of the head and neck Affected status: yes Allele origin: somatic	Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo Accession: SCV001450489.2 First in ClinVar: Dec 12, 2020 Last updated: Apr 13, 2025	Publications: PubMed (1) PubMed: 30816478 Age: 50-59 years Sex: male Geographic origin: Sri Lanka

Pathogenic (Oct 01, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001247047.30 First in ClinVar: May 12, 2020 Last updated: May 25, 2025	Comment: TP53: PS3, PM5, PP1:Moderate, PS2:Moderate, PS4:Moderate, PM2:Supporting Number of individuals with the variant: 2

Likely pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	Adrenocortical carcinoma Affected status: no Allele origin: somatic	Key Laboratory of Carcinogenesis and Cancer Invasion, Central South University Accession: SCV004046840.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024

Pathogenic (Aug 21, 2021) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	Breast carcinoma (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	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	Comment: Invasive Breast Carcinoma grade I EST= + PRO = + HER2 = + KI = 21% Zygosity: Single Heterozygote Sex: female

Likely pathogenic (Dec 01, 2018) N Not contributing to aggregate classification	no assertion criteria provided Method: research	Ovarian neoplasm Affected status: yes Allele origin: somatic	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

Pathogenic (Mar 19, 2021) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	B-cell chronic lymphocytic leukemia Affected status: yes Allele origin: somatic	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	Secondary finding: yes

Pathogenic (Jul 01, 2021) N Not contributing to aggregate classification	no assertion criteria provided Method: research	Gastric cancer Affected status: unknown Allele origin: germline	Laboratory for Genotyping Development, RIKEN Accession: SCV002758171.1 First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023	Publications: PubMed (1) PubMed: 36988593

Pathogenic (Oct 01, 2024) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	TP53-related disorder Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV005419153.1 First in ClinVar: Dec 07, 2024 Last updated: Dec 07, 2024	Publications: PubMed (1) PubMed: 33300245

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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 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:

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:

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 defecting 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:

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:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

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	-	-	-	-
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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.
Neoplasm		Oncogenic criteria provided, single submitter	Mar 4, 2025	RCV004668782.2

Submissions - Somatic

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.	More information 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 (ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022) Method: clinical testing	Neoplasm Affected status: unknown Allele origin: somatic	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV005094428.2 First In ClinVar: Aug 11, 2024 Last updated: Mar 11, 2025	Publications: PubMed (3) PubMed: 16861262‚ 23630318‚ 31395785

Comment:

Citations for somatic classification of this variant

Title	Author	Journal	Year	Link
A dominant-negative effect drives selection of TP53 missense mutations in myeloid malignancies.	Boettcher S	Science (New York, N.Y.)	2019	PMID: 31395785
Small molecule induced reactivation of mutant p53 in cancer cells.	Liu X	Nucleic acids research	2013	PMID: 23630318
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

Text-mined citations for rs121912666 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated May 25, 2025

ClinVar Genomic variation as it relates to human health

NM_000546.6(TP53):c.659A>G (p.Tyr220Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Conditions - Somatic

Submissions - Somatic

Citations for somatic classification of this variant

Text-mined citations for rs121912666 ...