2-47476435-G-A

Variant names:

• chr2-47476435-G-A
• rs63750232
• NM_000251.3:c.2074G>A

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.2074G>A​(p.Gly692Arg) 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. G692E) 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:3
• Conservation: PhyloP100: 9.60
• Publications: 14 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 25 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 13 benign, 27 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 chr2-47476436-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 265620.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 2-47476435-G-A is Pathogenic according to our data. Variant chr2-47476435-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 428477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000251.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	NM_000251.3	MANE Select	c.2074G>A	p.Gly692Arg	missense	Exon 13 of 16	NP_000242.1
	MSH2	NM_001406674.1		c.2074G>A	p.Gly692Arg	missense	Exon 13 of 18	NP_001393603.1
	MSH2	NM_001406631.1		c.2074G>A	p.Gly692Arg	missense	Exon 13 of 18	NP_001393560.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.2074G>A	p.Gly692Arg	missense	Exon 13 of 16	ENSP00000233146.2
	MSH2	ENST00000406134.5	TSL:1	c.2074G>A	p.Gly692Arg	missense	Exon 13 of 16	ENSP00000384199.1
	MSH2	ENST00000645506.1		c.2074G>A	p.Gly692Arg	missense	Exon 13 of 17	ENSP00000495455.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Jun 24, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G692R pathogenic mutation (also known as c.2074G>A), located in coding exon 13 of the MSH2 gene, results from a G to A substitution at nucleotide position 2074. The glycine at codon 692 is replaced by arginine, an amino acid with dissimilar properties. A similar mutation, c.2074G>C, which leads to the same amino acid change, p.G692R, has been reported in a Portuguese family meeting Amsterdam I criteria (Isidro G et al. Hum Mut. 2000 Jan;15(1):116). The glycine at position 692 is in a well conserved region, close to the ATP binding domain and functional analysis of the yeast equivalent demonstrated 5% steady-state levels of wildtype MSH2 and a loss of interaction with all MSH2 partners. A variant was considered to have a significant defect if levels were <40% of wildtype MSH2 (Gammie AE et al. Genetics. 2007 Oct;177(2): 707-21). In addition, the c.2074G>C variant has been classified as a likely pathogenic variant by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15; available at [www.insight-group.org/variants/classifications/]). Furthermore, all internal cases with the c.2074G>C mutation meet Bethesda or Amsterdam criteria and cases for which tumor studies were available showed concordance (Ambry Internal Data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.

Jun 02, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with arginine at codon 692 of the MSH2 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant disrupts DNA mismatch repair activity in a mouse embryonic stem cell-based assay (PMID: 26951660). While to our knowledge, this specific variant has not been reported in individuals affected with hereditary cancer in the literature, a different variant (c.2074G>C) resulting in the same amino acid change has been reported in individuals affected with Lynch syndrome-associated cancers (PMID: 10612836) and is considered to be disease-causing (ClinVar variation ID: 90878). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Apr 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 692 of the MSH2 protein (p.Gly692Arg). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly692 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12624141, 23454724, 23729658, 28135145, 29212164). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects MSH2 function (PMID: 17720936, 26951660). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is expected to disrupt MSH2 function. ClinVar contains an entry for this variant (Variation ID: 428477). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 10612836, 28577310; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	5.0	H
PhyloP100		9.6
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.98		Loss of catalytic residue at C693 (P = 0.1643)
MVP		0.99
MPC		0.033
ClinPred		1.0	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.97
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs63750232; hg19: chr2-47703574;