VCV000634770.11 - ClinVar

NM_000546.6(TP53):c.711G>T (p.Met237Ile)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic
Pathogenic (1); Likely pathogenic (3)

4 out of 6 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

Clinical impact

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

Tier I (Strong) for 2 tumor types

2 out of 2 submissions contributed to this classification

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.

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000546.6(TP53):c.711G>T (p.Met237Ile)

Variation ID: 634770 Accession: VCV000634770.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17p13.1 17: 7674252 (GRCh38) [ NCBI UCSC ] 17: 7577570 (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	Jun 17, 2019	Feb 23, 2026	Nov 18, 2025
Somatic - Clinical impact	Nov 22, 2025	Nov 22, 2025	Oct 3, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000546.6:c.711G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000537.3:p.Met237Ile	missense
NM_001126112.3:c.711G>T	NP_001119584.1:p.Met237Ile	missense
NM_001126113.3:c.711G>T	NP_001119585.1:p.Met237Ile	missense
NM_001126114.3:c.711G>T	NP_001119586.1:p.Met237Ile	missense
NM_001126115.2:c.315G>T	NP_001119587.1:p.Met105Ile	missense
NM_001126116.2:c.315G>T	NP_001119588.1:p.Met105Ile	missense
NM_001126117.2:c.315G>T	NP_001119589.1:p.Met105Ile	missense
NM_001126118.2:c.594G>T	NP_001119590.1:p.Met198Ile	missense
NM_001276695.3:c.594G>T	NP_001263624.1:p.Met198Ile	missense
NM_001276696.3:c.594G>T	NP_001263625.1:p.Met198Ile	missense
NM_001276697.3:c.234G>T	NP_001263626.1:p.Met78Ile	missense
NM_001276698.3:c.234G>T	NP_001263627.1:p.Met78Ile	missense
NM_001276699.3:c.234G>T	NP_001263628.1:p.Met78Ile	missense
NM_001276760.3:c.594G>T	NP_001263689.1:p.Met198Ile	missense
NM_001276761.3:c.594G>T	NP_001263690.1:p.Met198Ile	missense
NC_000017.11:g.7674252C>A
NC_000017.10:g.7577570C>A
NG_017013.2:g.18299G>T
LRG_321:g.18299G>T
LRG_321t1:c.711G>T	LRG_321p1:p.Met237Ile

... more HGVS ... less HGVS

Protein change

M105I, M198I, M237I, M78I

Other names

Canonical SPDI

NC_000017.11:7674251:C:A

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.

Links

ClinGen: CA287488024 dbSNP: rs587782664 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	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.
Ovarian neoplasm	Likely pathogenic (1)	no assertion criteria provided	Dec 1, 2018	RCV000785508.2
Hereditary cancer-predisposing syndrome	Likely pathogenic (1)	criteria provided, single submitter	Jan 14, 2020	RCV002370058.2
Malignant tumor of urinary bladder	Pathogenic (1)	no assertion criteria provided	-	RCV003332249.1
Adrenocortical carcinoma, hereditary	Likely pathogenic (1)	criteria provided, single submitter	Aug 30, 2022	RCV003472321.1
Li-Fraumeni syndrome	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Nov 18, 2025	RCV003509608.5

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.
Likely pathogenic (Jan 14, 2020) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Hereditary cancer-predisposing syndrome	Ambry Genetics Accession: SCV002668328.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: show The p.M237I variant (also known as c.711G>T), located in coding exon 6 of the TP53 gene, results from a G to T substitution at nucleotide position 711. The methionine at codon 237 is replaced by isoleucine, an amino acid with highly similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation in yeast based assays (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9). Additional studies conducted in human cell lines indicate this alteration has a dominant negative effect and is deficient at growth suppression (Kotler E et al. Mol. Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). 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 majority of available evidence to date, this variant is likely to be 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

Likely pathogenic (Aug 30, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Adrenocortical carcinoma, hereditary	Baylor Genetics Accession: SCV004204274.1 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

Likely pathogenic (Jul 22, 2025) C Contributing to aggregate classification	criteria provided, single submitter (CanVIG TP53 Gene Specific V1.6)	Li Fraumeni Syndrome	Genetics Laboratory, Great Ormond Street Hospital NHS Foundation Trust, North Thames Genomic Laboratory Hub Accession: SCV006333417.1 First in ClinVar: Sep 27, 2025 Last updated: Sep 27, 2025	Comment: show PM2_supporting, PS3_strong, PM1_moderate (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 (Nov 18, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Li-Fraumeni syndrome	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004365008.3 First in ClinVar: Feb 14, 2024 Last updated: Feb 23, 2026	Publications: PubMed (7) PubMed: 11370630‚ 11399766‚ 12826609‚ 20407015‚ 22109999‚ 29979965‚ 30224644 Comment: show This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 237 of the TP53 protein (p.Met237Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Li-Fraumeni syndrome (PMID: 11370630; internal data). ClinVar contains an entry for this variant (Variation ID: 634770). 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: 11399766, 12826609, 20407015). This variant disrupts the p.Met237 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12826609, 22109999, 29979965, 30224644; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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

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: SCV000924080.1 First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019	Observation: 1 Collection method: research Allele origin: somatic Affected status: yes more Observation 1 Collection method: research Allele origin: somatic Affected status: yes Platform type: next-gen sequencing

Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	Malignant tumor of urinary bladder	Laboratory of Urology, Hospital Clinic de Barcelona Accession: SCV004040514.1 First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023	Observation: 1 Collection method: research Allele origin: somatic Affected status: yes Observation 1 Collection method: research Allele origin: somatic Affected status: yes

Comment:

The p.M237I variant (also known as c.711G>T), located in coding exon 6 of the TP53 gene, results from a G to T substitution at nucleotide position 711. The methionine at codon 237 is replaced by isoleucine, an amino acid with highly similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation in yeast based assays (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9). Additional studies conducted in human cell lines indicate this alteration has a dominant negative effect and is deficient at growth suppression (Kotler E et al. Mol. Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). 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 majority of available evidence to date, this variant is likely to be pathogenic.

Comment:

Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in primary intracranial sarcoma, DICER1-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 (PMID: 12826609). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 29881993, 32291395, 36966138, 31487013, 34674226).

Comment:

Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in medulloblastoma SHH activated and TP53 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: 15781620, 12826609, 27328919). 4) Diagnostic for a specific tumor type/classification according to professional guidelines (Evidence Level A; PMIDs: 21163964, 22820256, 22832583, 22722829, 28726821, 31574483).

Comment:

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 237 of the TP53 protein (p.Met237Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Li-Fraumeni syndrome (PMID: 11370630; internal data). ClinVar contains an entry for this variant (Variation ID: 634770). 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: 11399766, 12826609, 20407015). This variant disrupts the p.Met237 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12826609, 22109999, 29979965, 30224644; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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
Assessment of p53 functional activity in tumor cells and histologically normal mucosa from patients with head and neck squamous cell carcinoma.	Van der Vorst S	Head & neck	2012	PMID: 22109999
Altered-function p53 missense mutations identified in breast cancers can have subtle effects on transactivation.	Jordan JJ	Molecular cancer research : MCR	2010	PMID: 20407015
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
Functional interaction of p53 and BLM DNA helicase in apoptosis.	Wang XW	The Journal of biological chemistry	2001	PMID: 11399766
Detection of 11 germline inactivating TP53 mutations and absence of TP63 and HCHK2 mutations in 17 French families with Li-Fraumeni or Li-Fraumeni-like syndrome.	Bougeard G	Journal of medical genetics	2001	PMID: 11370630

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.
Primary intracranial sarcoma, DICER1-mutant	Tier I (Strong) - diagnostic - supports diagnosis (1)		Dec 22, 2023	RCV006254153.1
Medulloblastoma SHH activated and TP53 mutant	Tier I (Strong) - diagnostic - supports diagnosis (1)		Oct 3, 2024	RCV006254154.1

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 (Dec 22, 2023) C Contributing to aggregate classification	criteria provided, single submitter (AMP/ASCO/CAP Guidelines, 2017)	Primary intracranial sarcoma, DICER1-mutant	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital Accession: SCV007104688.1 First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025	Publications: PubMed (6) PubMed: 12826609‚ 29881993‚ 31487013‚ 32291395‚ 34674226‚ 36966138 Comment: show Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in primary intracranial sarcoma, DICER1-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 (PMID: 12826609). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 29881993, 32291395, 36966138, 31487013, 34674226). (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 03, 2024) C Contributing to aggregate classification	criteria provided, single submitter (AMP/ASCO/CAP Guidelines, 2017)	Medulloblastoma SHH activated and TP53 mutant	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital Accession: SCV007105567.1 First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025	Publications: PubMed (9) PubMed: 12826609‚ 15781620‚ 21163964‚ 22722829‚ 22820256‚ 22832583‚ 27328919‚ 28726821‚ 31574483 Comment: show Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in medulloblastoma SHH activated and TP53 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: 15781620, 12826609, 27328919). 4) Diagnostic for a specific tumor type/classification according to professional guidelines (Evidence Level A; PMIDs: 21163964, 22820256, 22832583, 22722829, 28726821, 31574483). (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

Comment:

Citations for somatic classification of this variant

Title	Author	Journal	Year	Link
Genomic characterization of DICER1-associated neoplasms uncovers molecular classes.	Kommoss FKF	Nature communications	2023	PMID: 36966138
Primary central nervous system sarcoma with DICER1 mutation-treatment results of a novel molecular entity in pediatric Peruvian patients.	Diaz Coronado RY	Cancer	2022	PMID: 34674226
DICER1-associated central nervous system sarcoma in children: comprehensive clinicopathologic and genetic analysis of a newly described rare tumor.	Kamihara J	Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc	2020	PMID: 32291395
Medulloblastoma in the age of molecular subgroups: a review.	Juraschka K	Journal of neurosurgery. Pediatrics	2019	PMID: 31574483
Two cases of primary supratentorial intracranial rhabdomyosarcoma with DICER1 mutation which may belong to a "spindle cell sarcoma with rhabdomyosarcoma-like feature, DICER1 mutant".	Sakaguchi M	Brain tumor pathology	2019	PMID: 31487013
Primary intracranial spindle cell sarcoma with rhabdomyosarcoma-like features share a highly distinct methylation profile and DICER1 mutations.	Koelsche C	Acta neuropathologica	2018	PMID: 29881993
The whole-genome landscape of medulloblastoma subtypes.	Northcott PA	Nature	2017	PMID: 28726821
TP53 Variations in Human Cancers: New Lessons from the IARC TP53 Database and Genomics Data.	Bouaoun L	Human mutation	2016	PMID: 27328919
Dissecting the genomic complexity underlying medulloblastoma.	Jones DT	Nature	2012	PMID: 22832583
Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations.	Pugh TJ	Nature	2012	PMID: 22820256
Novel mutations target distinct subgroups of medulloblastoma.	Robinson G	Nature	2012	PMID: 22722829
The genetic landscape of the childhood cancer medulloblastoma.	Parsons DW	Science (New York, N.Y.)	2011	PMID: 21163964
Lack of correlation between p53-dependent transcriptional activity and the ability to induce apoptosis among 179 mutant p53s.	Kakudo Y	Cancer research	2005	PMID: 15781620
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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Text-mined citations for rs587782664 ...

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 Apr 13, 2026