rs772491283

Positions:

• chr2-47476444-G-A
• chr2-47476444-G-C
• chr2-47476444-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000251.3(MSH2):​c.2083G>A​(p.Val695Met) 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 Pathogenic (★★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 9.60

Genes affected

MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a strand (size 8) in uniprot entity MSH2_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000251.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968
• PP5: Variant 2-47476444-G-A is Pathogenic according to our data. Variant chr2-47476444-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 633496.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47476444-G-A is described in Lovd as [Likely_pathogenic]. Variant chr2-47476444-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2083G>A	p.Val695Met	missense_variant	13/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.2083G>A	p.Val695Met	missense_variant	13/16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Sep 18, 2024

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 33357406]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Lynch syndrome Pathogenic:1

Pathogenic, reviewed by expert panel

curation

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Oct 18, 2018

Multifactorial likelihood analysis posterior probability > 0.99 (0.998) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The p.V695M variant (also known as c.2083G>A), located in coding exon 13 of the MSH2 gene, results from a G to A substitution at nucleotide position 2083. The valine at codon 695 is replaced by methionine, an amino acid with highly similar properties. This alteration has been classified as pathogenic using the following lines of evidence: in silico prediction models, segregation with disease, and clinical phenotype which includes tumor characteristics (Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was determined to be functionally deleterious (Jia X et al. Am J Hum Genet, 2021 01;108:163-175). This variant is considered to be rare based on population 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D;.;.;.
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.9	H;.;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.9	D;D;.;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;.;D
Polyphen		1.0	D;.;.;D
Vest4		0.89
MutPred		0.88		Loss of catalytic residue at E698 (P = 0.2636);.;Loss of catalytic residue at E698 (P = 0.2636);Loss of catalytic residue at E698 (P = 0.2636);
MVP		0.96
MPC		0.035
ClinPred		1.0	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.95

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

Other links and lift over

dbSNP: rs772491283; hg19: chr2-47703583;