rs765848205

chr17-7674253-A-Cchr17-7674253-A-Gchr17-7674253-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_000546.6(TP53):c.710T>G(p.Met237Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). 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: 30)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 9.23

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 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 chr17-7674252-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 142714.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.710T>G	p.Met237Arg	missense_variant	7/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.710T>G	p.Met237Arg	missense_variant	7/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 04, 2022

This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 237 of the TP53 protein (p.Met237Arg). This variant is not present in population databases (gnomAD no frequency). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 7651740, 9635828, 16861262, 29979965). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function. ClinVar contains an entry for this variant (Variation ID: 419524). This variant has not been reported in the literature in individuals affected with TP53-related conditions. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 29, 2015

This variant is denoted TP53 c.710T>G at the cDNA level, p.Met237Arg (M237R) at the protein level, and results in the change of a Methionine to an Arginine (ATG>AGG). While this variant has not, to our knowledge, been published in the literature as either a germline pathogenic variant or benign polymorphism, TP53 Met237Arg has been reported as a somatic variant in hematologic, pancreatic and prostate cancers (COSMIC). This variant is reported in the IARC TP53 database with partially-functional transactivation activity based on functional assays by Kato et al. (2003). Additional yeast and mammalian assays performed by Dearth et al. (2007) demonstrated that the activity of TP53 Met237Arg was similar to wild type. TP53 Met237Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Methionine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Met237Arg occurs at a position that is conserved across species and is located within the domain interaction with HIPK1, required for interaction with ZNF385A and AXIN1. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available information, it is unclear whether TP53 Met237Arg is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 12, 2021

The p.M237R variant (also known as c.710T>G), located in coding exon 6 of the TP53 gene, results from a T to G substitution at nucleotide position 710. The methionine at codon 237 is replaced by arginine, an amino acid with similar properties. This 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 are equivocal about this variant's ability to suppress cell growth (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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
Cadd	Pathogenic	33
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D;D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.;D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
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	0.90	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.7	D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D
REVEL	Pathogenic	0.95
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;.
Polyphen		1.0	D;.;.;.;.;.;.;.;.;D;.;D;B;D;.;.;D;.;.;.;D
Vest4		0.97
MutPred		0.88		Gain of catalytic residue at M237 (P = 0.0283);Gain of catalytic residue at M237 (P = 0.0283);.;.;.;.;.;.;.;Gain of catalytic residue at M237 (P = 0.0283);.;Gain of catalytic residue at M237 (P = 0.0283);Gain of catalytic residue at M237 (P = 0.0283);Gain of catalytic residue at M237 (P = 0.0283);.;.;Gain of catalytic residue at M237 (P = 0.0283);.;.;.;.;
MVP		0.99
MPC		0.47
ClinPred		1.0	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.58		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.58		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs765848205; hg19: chr17-7577571; COSMIC: COSV53037741; COSMIC: COSV53037741;