2-47416365-G-C

Position:

• chr2-47416365-G-C

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PS1 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000251.3(MSH2):​c.1012G>C​(p.Gly338Arg) 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. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G338E) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.81

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 22 ACMG points.

• PS1: Transcript NM_000251.3 (MSH2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a helix (size 11) in uniprot entity MSH2_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_000251.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-47416366-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• PP5: Variant 2-47416365-G-C is Pathogenic according to our data. Variant chr2-47416365-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 232810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.1012G>C	p.Gly338Arg	missense_variant	6/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1012G>C	p.Gly338Arg	missense_variant	6/16	1	NM_000251.3	ENSP00000233146	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lynch syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Aug 09, 2023

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

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 19, 2020

Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies demonstrated that the yeast equivalent of MSH2 Gly338Arg results in low levels of MSH2 protein and loss of interaction with MSH2 partners (Gammie 2007); This variant is associated with the following publications: (PMID: 22290698, 16736289, 17720936, 23760103, 21665242, 16995940, 15629722, 26843368, 29423084, 28944238, 31391288, 30877237, 23612316, 29967423, 31679916) -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 25, 2020

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects MSH2 protein function (PMID: 17720936). This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 16736289, 23612316, external communication, Invitae). It has also been observed to segregate with disease in related individuals (Invitae). ClinVar contains an entry for this variant (Variation ID: 232810). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 338 of the MSH2 protein (p.Gly338Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 01, 2021

The p.G338R pathogenic mutation (also known as c.1012G>C), located in coding exon 6 of the MSH2 gene, results from a G to C substitution at nucleotide position 1012. The glycine at codon 338 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been identified in an individual whom met Bethesda criteria but whose tumor was MSS and showed presence of MSH2 and MLH1 by immunohistochemistry (IHC) (Spaepen M et al. Fam. Cancer 2006;5(2):179-89). However, this alteration has also been reported in the literature in an individual with a family history of colon cancer whom met Bethesda criteria and had an MSH2-absent endometrioid carcinoma at age 54 along with colon cancer at age 42 (Moline J et al., Gynecol. Oncol. 2013 Jul; 130(1):121-6). This alteration has also been detected in individuals with a family history that met Amsterdam criteria and/or had colorectal tumors that displayed loss of both MSH2/MSH6 protein expression by IHC (Ambry internal data; Pearlman R et al. J. Med. Genet., 2019 Jul;56:462-470). This alteration was also identified in conjunction with a somatic mutation in MSH2 in an individual with early-onset colorectal cancer that was MSI-H and showed loss of both MSH2/MSH6 protein expression by IHC (Ambry internal data). In a study that quantified tumor characteristics to assess pathogenicity for germline mismatch repair gene variants, this variant was reported in two individuals whose Lynch syndrome-associated tumor demonstrated loss of MSH2 expression on IHC (Ambry internal data; Li S et al. J. Med. Genet. 2020 Jan;57:62-69). Functional studies using the yeast equivalent of this MSH2 variant demonstrated reduced mismatch repair activity, expression, and loss of interaction with MSH6 (Gammie AE et al. Genetics, 2007 Oct;177:707-21). Furthermore, 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.5	H;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-7.8	D;D;.;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Uncertain	0.0020	D;D;.;D
Polyphen		1.0	D;.;.;D
Vest4		0.98
MutPred		0.96		Gain of MoRF binding (P = 0.0256);.;Gain of MoRF binding (P = 0.0256);Gain of MoRF binding (P = 0.0256);
MVP		0.99
MPC		0.033
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.99
gMVP		0.89

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: rs63751004; hg19: chr2-47643504;