chr17-7674254-T-C

Position:

chr17-7674254-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The ENST00000269305.9(TP53):c.709A>G(p.Met237Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,670 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M237I) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TP53
ENST00000269305.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:5

Conservation

PhyloP100: 7.94

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 14 uncertain in ENST00000269305.9

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-7674252-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 142714.Status of the report is reviewed_by_expert_panel, 3 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.709A>G	p.Met237Val	missense_variant	7/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 linkuse as main transcript	c.709A>G	p.Met237Val	missense_variant	7/11	1	NM_000546.6	ENSP00000269305	P1	P04637-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461670

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727154

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:1Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 28, 2024	The p.M237V variant (also known as c.709A>G), located in coding exon 6 of the TP53 gene, results from an A to G substitution at nucleotide position 709. The methionine at codon 237 is replaced by valine, an amino acid with highly similar properties. The p.M237V variant is in the DNA binding domain of the TP53 protein and is reported to have partially 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). TP53 p.M237V was reported in a woman with bilateral breast cancer at ages 22 and 41 (Turner SA et al. Genet Med, 2019 02;21:426-430). Based on internal structural analysis, p.M237V disrupts important hydrogen bonding interactions and the local structure of a functionally important loop near a zinc-binding motif within the DNA binding site of TP53 (Ambry internal data; Golovenko D et al. Structure. 2018 Sep 4;26(9):1237-1250; Lukman S et al. PLoS One. 2013 Nov 12;8(11); Butler JS and Loh SN. Biochemistry. 2003 Mar 4;42(8):2396-403; Bullock AN, Henckel J, Fersht AR. Oncogene. 2000 Mar 2;19(10):1245-56). This alteration was observed 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel in a patient who met LFS criteria, and has been observed in at least one individual with a personal and/or family history that is consistent with TP53-related disease (Susswein LR et al. Genet Med, 2016 08;18:823-32; Ambry internal data). Another alteration at the same codon, p.M237I (c.711G>A), has been described in a classic Li Fraumeni syndrome (LFS) case (Fortes FP et al. Braz. J. Med. Biol. Res., 2015 Jul;48:610-5). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 14, 2023	This missense variant replaces methionine with valine at codon 237 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 partially functional in yeast transactivation assay (PMID: 12826609, DOI: 10.1182/blood-2019-124622), and non-functional in human cell growth assays and exhibit dominant negative effect (PMID: 29979965, 30224644). This variant and other missense variants occurring at the same codon, p.Met237Lys and p.Met237lIe, showed significantly reduced transcriptional activity in yeast assays (Fischer 2019, dissertation, University of Toronto). This variant has been reported in an individual affected with breast cancer and meeting clinical testing criteria for Li-Fraumeni syndrome (PMID: 26681312) and in an individual affected with early-onset bilateral breast cancer meeting the Chompret criteria for Li-Fraumeni syndrome (PMID: 29875428). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, the available evidence is insufficient to determine the role of this variant in hereditary cancer conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 02, 2017

This variant is denoted TP53 c.709A>G at the cDNA level, p.Met237Val (M237V) at the protein level,and results in the change of a Methionine to a Valine (ATG>GTG). This variant has been reported as a somatic variantin multiple cancer types including breast, colon and lung (Vega 1997, Deissler 2004, Malhotra 2013). Although anothervariant at this residue, TP53 Met237Ile, has been shown to severely impact transactivation in yeast-based assays(Kato 2003, Dearth 2007, Monti 2011), TP53 Met237Val is reported as having partially functional transactivation in theInternational Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53Met237Val was not observed in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBIExome Sequencing Project). Since Methionine and Valine share similar properties, this is considered a conservativeamino acid substitution. TP53 Met237Val occurs at a position that is conserved across species and is located in theDNA-binding domain (Bode 2004). In silico analyses predict that this variant is probably damaging to protein structureand function. Based on currently available evidence, it is unclear whether TP53 Met237Val is a pathogenic or benignvariant. We consider it to be a variant of uncertain significance. -

Li-Fraumeni syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 18, 2022

- -

Li-Fraumeni syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 18, 2023

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 237 of the TP53 protein (p.Met237Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 26681312, 28973705). ClinVar contains an entry for this variant (Variation ID: 182934). 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: 12826609). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.46

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.70

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

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

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

M_CAP

Pathogenic

0.81

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

1.0

MutationAssessor

Uncertain

2.4

.;.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.8

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

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0010

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.91

MutPred

0.89

Gain of catalytic residue at M237 (P = 0.0545);Gain of catalytic residue at M237 (P = 0.0545);.;.;.;.;.;.;.;Gain of catalytic residue at M237 (P = 0.0545);.;Gain of catalytic residue at M237 (P = 0.0545);Gain of catalytic residue at M237 (P = 0.0545);Gain of catalytic residue at M237 (P = 0.0545);.;.;Gain of catalytic residue at M237 (P = 0.0545);.;.;.;.;

MVP

0.97

MPC

0.39

ClinPred

0.99

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

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