17-7673806-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000546.6(TP53):c.814G>A(p.Val272Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,754 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 Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V272E) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:20

Conservation

PhyloP100: 6.17

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 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 chr17-7673806-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.959

PP5

Variant 17-7673806-C-T is Pathogenic according to our data. Variant chr17-7673806-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 185814.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.814G>A	p.Val272Met	missense_variant	8/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9 linkuse as main transcript	c.814G>A	p.Val272Met	missense_variant	8/11	1	NM_000546.6	P1	P04637-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152048

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250892

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135628

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461754

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727178

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152048

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74256

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000106

Hom.:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 10, 2020	The p.Val272Met variant in TP53 has been reported in 3 individuals with Li-Fraumeni syndrome or adrenocortical carcinoma and one individual with rhabdomyosarcoma with a de novo mutation (Bougeard 2008 PMID: 18511570, Raymond 2013 PMID: 23175693, Wasserman 2015 PMID: 25584008, Renaux-Petel 2018 PMID: 29070607). It has also been identified in 0.0009% (1/113432) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 185814). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant disrupts the transcriptional transactivation function of the TP53 protein in a temperature sensitive manner (da Costa 2012 PMID: 23165212, Jia 1997 PMID: 9290701, Dearth 2007 PMID: 16861262, Ponchel 1998 PMID: 9635828, Jagosova 2012 PMID: 22710932); however, these types of assays may not accurately represent biological function. 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 LFS. DISEASE. ACMG/AMP Criteria applied: PM2, PS4_Moderate, PP3, PS3_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 24, 2023	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 272 of the TP53 protein (p.Val272Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 18511570, 23175693, 25584008, 29070607). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 185814). Advanced modeling performed at Invitae incorporating data from internal and/or published 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: 9290701, 9635828, 12826609, 16861262, 22710932). For these reasons, this variant has been classified as Pathogenic. -

Li-Fraumeni syndrome 1

Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen TP53 Variant Curation Expert Panel, ClinGen	Mar 18, 2022	This variant has >10 observations as a somatic hotspot variant in tumors (PM1; cancerhotspots.org v(2)). Transactivation assays show a low functioning allele according to Kato, et al. and there is evidence of a dominant negative effect and loss of function according to Giacomelli, et al. (PS3; PMID: 12826609, 30224644). This variant has been reported in 4 probands meeting Chompret criteria (PS4_Moderate; PMID: 25584008, 23175693, IARC, NIH). There are de novo observations in 2 probands with childhood rhabdomyosarcoma, osteosarcoma, without parental confirmation (PM6_Strong; PMID: IARC, NIH). In summary, TP53 c.814G>A (p.Val272Met) meets criteria to be classified as pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM1, PS3, PS4_Moderate, PM6_Strong. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 20, 2024	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 7651740, 9635828, 15037740, 16861262]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Squamous cell carcinoma of the skin

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Gastric adenocarcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Breast neoplasm

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 11, 2023

Published functional studies demonstrate a damaging effect: non-functional transactivation, lack of growth suppression and apoptotic activities, and a dominant-negative effect per some reporters (Ponchel et al., 1998; Kato et al., 2003; Baroni et al., 2004; Dearth et al., 2007; Giacomelli et al., 2018; Kotler et al., 2018); Identified in individuals reported to have Li-Fraumeni-related cancers (Bougeard et al., 2008; Raymond et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16322298, 7651740, 9635828, 26230955, 27121310, 21643842, 15037740, 16861262, 11429700, 10753186, 9096669, 19003964, 9290701, 14559903, 26425688, 25787918, 27101868, 27926791, 21319261, 15221786, 25584008, 11870884, 25407396, 28861920, 30720243, 30840781, 34426522, 29997966, 27311873, 31200822, Kim2019[article], 32371587, 33531134, 28243320, 32260152, 35974385, 23175693, 30914417, 18511570, 12826609, 29979965, 30224644, 29070607, 15510160, 32658383, 34544131, 34382015, 34306021, 34583722, 34544143, 32165485, 32164171) -

Papillary renal cell carcinoma type 1

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Medulloblastoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Ovarian serous cystadenocarcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Multiple myeloma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Malignant neoplasm of body of uterus

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Neoplasm of ovary

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

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

Dec 01, 2018

- -

Pancreatic adenocarcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Lung adenocarcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Transitional cell carcinoma of the bladder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 10, 2024

The p.V272M pathogenic mutation (also known as c.814G>A), located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 814. The valine at codon 272 is replaced by methionine, an amino acid with highly similar properties. This alteration has been detected in a French family with features suggestive of Li-Fraumeni syndrome, a patient diagnosed with rhabdomyosarcoma at age 1 and osteosarcoma at age 2, as well as a patient diagnosed with medulloblastoma at age 3 (Bougeard G et al. J. Med. Genet. 2008 Aug;45(8):535-8; Renaux-Petel M et al. J. Med. Genet. 2017 Oct 25). This alteration was also identified in a patient with late onset adrenal cortical carcinoma (Raymond VM et al. J. Clin. Endocrinol. Metab. 2013 Jan; 98(1):E119-25). The p.V272M alteration has been reported as a somatic alteration in a variety of tumors (Marinelli M et al. Haematologica 2013 Mar; 98(3):371-5; Chiaretti S et al. Genes Chromosomes Cancer 2011 Apr; 50(4):263-74; Chang MT et al. Cancer Discov. 2018 02;8:174-183). This alteration is a well-known temperature sensitive alteration that causes abnormal protein folding and prevents DNA binding at temperatures above 37 degrees Celsius (da Costa NM et al. Cell Cycle 2012 Dec;11(24):4570-8). Functional studies have demonstrated that this alteration interferes with p53 up-regulation in response to DNA damaging agents and shows loss of transactivation capacity in yeast based assays (Barnas Cet al. Int. J. Cancer 1997 Mar;71(1):79-87). 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 not well 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. -

Squamous cell carcinoma of the head and neck

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Neoplasm of the large intestine

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.50

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.69

D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.75

T;T;T;T;T;T;T;.;.;.;T;T;.;T;T;T;T;T;T

M_CAP

Pathogenic

0.47

MetaRNN

Pathogenic

0.96

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.95

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-2.0

N;.;.;.;.;.;.;.;N;.;.;N;N;.;.;N;.;.;N

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0020

D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D

Sift4G

Uncertain

0.017

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0

.;.;.;.;.;.;.;.;D;.;D;D;D;.;.;D;.;.;.

Vest4

0.62

MutPred

0.87

Loss of sheet (P = 0.1158);.;.;.;.;.;.;.;Loss of sheet (P = 0.1158);.;Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);.;.;Loss of sheet (P = 0.1158);.;.;.;

MVP

0.97

MPC

0.39

ClinPred

0.94

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over