2-47416365-G-C

Variant names:

• chr2-47416365-G-C
• rs63751004
• NM_000251.3:c.1012G>C

Variant summary

Our verdict is Pathogenic. The variant received 26 ACMG points: 26P and 0B. PS1_Very_Strong 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. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G338V) has been classified as Likely 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
• Publications: 13 publications found

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]

MSH2 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• Lynch syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• Muir-Torre syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• mismatch repair cancer syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• ovarian cancer

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 26 ACMG points.

• PS1: Transcript NM_000251.3 (MSH2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 11 benign, 38 uncertain 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-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 568928.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 232810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.1012G>C	p.Gly338Arg	missense_variant	Exon 6 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1012G>C	p.Gly338Arg	missense_variant	Exon 6 of 16	1	NM_000251.3	ENSP00000233146.2

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

Aug 09, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 19, 2020

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 25, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 15, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;.;.;.
PhyloP100		9.8
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
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs63751004; hg19: chr2-47643504;