17-7674885-C-T

Variant names:

• chr17-7674885-C-T
• rs730882025
• NM_000546.6:c.646G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000546.6(TP53):​c.646G>A​(p.Val216Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V216L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12 U:2 O:1
• Conservation: PhyloP100: 7.91
• Publications: 265 publications found

Genes affected

TP53 (HGNC:11998): (tumor protein p53) This gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations in this gene are associated with a variety of human cancers, including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of this gene and the use of alternate promoters result in multiple transcript variants and isoforms. Additional isoforms have also been shown to result from the use of alternate translation initiation codons from identical transcript variants (PMIDs: 12032546, 20937277). [provided by RefSeq, Dec 2016]

TP53 Gene-Disease associations (from GenCC):

• breast cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• Li-Fraumeni syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
• Li-Fraumeni syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
• adrenocortical carcinoma, hereditary

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• bone marrow failure syndrome 5

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• colorectal cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• choroid plexus carcinoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 25 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 11 benign, 28 uncertain in NM_000546.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-7674885-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 406596.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 17-7674885-C-T is Pathogenic according to our data. Variant chr17-7674885-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 182965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.646G>A	p.Val216Met	missense_variant	Exon 6 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.646G>A	p.Val216Met	missense_variant	Exon 6 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12 Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome Pathogenic:3

Apr 02, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Val216Met variant in TP53 has been reported in two individuals with TP53-related tumors and one individual with a family history of TP53-related tumors (Castera 2014, Bougeard 2015, Zerdoumi 2017). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 182965). It has also been reported as a common somatic mutation across multiple tumor types (COSMIC Database, https://cancer.sanger.ac.uk/cosmic/). In vitro functional studies provide some evidence that this variant impacts protein transactivation function (Slovackova 2010, Zerdoumi 2017); however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analysis support that this variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Li-Fraumeni syndrome. ACMG/AMP Criteria applied: PM2, PS3_Moderate, PP3, PS4_Supporting.

Sep 17, 2020

Cancer Variant Interpretation Group UK, Institute of Cancer Research, London

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Data included in classification: UK family: 4 generation classic LFS family including multiple sarcomas Literature: (i) Bougeard 2015: 1 child (?age) with ACC , (ii) Zerdoumi 2017: 1 adult male age 30y with alveloar rhabdo age 3y & soft tissue sarcoma age 17y. Both index cases & fulfil Chompret (nil known re FHx) (PS4_mod). This variant is absent from gnomAD (PM2_sup). AGvGD = C15 , Bayes Del = 0.5501. PP3_sup. x81 somatic in IARC (PM1_sup). Kato – non functional, DNE + LOF (Giacomelli) , Kotler - RFS score = 0.2 → compromised function. (PS3_strong)

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 216 of the TP53 protein (p.Val216Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with breast and/or ovarian cancer and clinical features of Li-Fraumeni syndrome (PMID: 24549055, 25669829, 26014290; internal data). ClinVar contains an entry for this variant (Variation ID: 182965). 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, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic.

Li-Fraumeni syndrome 1 Pathogenic:2 Uncertain:1

Aug 16, 2024

Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 11, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].

Apr 25, 2018

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Adrenocortical carcinoma, hereditary Pathogenic:2

Sep 10, 2025

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 29, 2021

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:2

Nov 21, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: severely impacted transcriptional activation and expression of typical p53 targets as well as impaired growth suppression ability (PMID: 12826609, 30224644, 29979965, 20505364, 17724467, 21232794); Identified in patients with history consistent with pathogenic variants in this gene referred for genetic testing at GeneDx and in published literature (PMID: 32658383, 35974385, 28472496, 26014290); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21232794, 26014290, 20364130, 12826609, 18348286, 26619011, 16322298, 26567765, 25669829, 10949938, 19850740, 26787237, 11590071, 12673679, 28472496, 24549055, 17724467, 30720243, 30840781, 29979965, 15510160, 30224644, 32658383, 35974385, 20505364, 28369373)

Nov 25, 2019

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the TP53 gene demonstrated a sequence change, c.646G>A, in exon 6 that results in an amino acid change, p.Val216Met. The p.Val216Met change has not been described in population databases (gnomAD, ExAC). This sequence change has been identified in a child with adrenocortical carcinoma (PMID: 26014290). Functional studies revealed that the p.Val216Met change results in a drastic change of p53 transcriptional activity, similar to that of dominant-negative mutations (PMID: 28369373). The p.Val216Met change affects a highly conserved amino acid residue located in a domain of the TP53 protein that is known to be functional. The p.Val216Met substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL)." DNA sequence analysis of the TP53 gene demonstrated a sequence change, c.646G>A, in exon 6 that results in an amino acid change, p.Val216Met. The p.Val216Met change has not been described in population databases (gnomAD, ExAC). This sequence change has been identified in a child with adrenocortical carcinoma (PMID: 26014290). Functional studies revealed that the p.Val216Met change results in a drastic change of TP53 transcriptional activity, similar to that of dominant-negative mutations (PMID: 28369373). The p.Val216Met change affects a highly conserved amino acid residue located in a domain of the TP53 protein that is known to be functional. The p.Val216Met substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL).

Hereditary cancer-predisposing syndrome Pathogenic:2

Sep 04, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V216M pathogenic mutation (also known as c.646G>A), located in coding exon 5 of the TP53 gene, results from a G to A substitution at nucleotide position 646. The valine at codon 216 is replaced by methionine, an amino acid with highly similar properties. This variant was previously detected in a child diagnosed with adrenocorticol carcinoma and in an individual with a personal history of alveolar rhabdomyosarcoma and soft tissue sarcoma (Bougeard G et al. J. Clin. Oncol. 2015 Jul;33:2345-52; Zerdoumi Y et al. Hum Mol Genet, 2017 07;26:2812). 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). 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). Based on internal structural analysis, this variant results in destabilization of the TP53 DNA binding domain (Kitayner M et al. Nat. Struct. Mol. Biol. 2010 Apr;17:423-9). 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). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analyses. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Jan 14, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces valine with methionine at codon 216 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown the mutant protein to be defective in transactivation assays (PMID: 12826609, 17724467, 19850740, 21232794) and in human cell growth assays (PMID: 29979965, 30224644). This variant has been reported in individuals satisfying the Chompret criteria for Li-Fraumeni syndrome (PMID: 26014290, 28369373, 32658383). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

Ovarian neoplasm Pathogenic:1

Dec 01, 2018

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

not specified Uncertain:1

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Neoplasm Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.;D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.87
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Benign	0.0	.;.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.;.
PhyloP100		7.9
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.8	D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D
Sift	Pathogenic	0.0	D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Vest4		0.96
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.95
gMVP		0.69
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs730882025; hg19: chr17-7578203; COSMIC: COSV52671096; COSMIC: COSV52671096;