chr2-47476435-G-C

Position:

• chr2-47476435-G-C

Variant summary

Our verdict is Pathogenic. Variant got 26 ACMG points: 26P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000233146.7(MSH2):​c.2074G>C​(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. 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 Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G692V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 ENST00000233146.7 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4
• 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 26 ACMG points.

• PS1: Transcript ENST00000233146.7 (MSH2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 428477
• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 14 uncertain in ENST00000233146.7
• 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-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 90880.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 2-47476435-G-C is Pathogenic according to our data. Variant chr2-47476435-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 90878.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47476435-G-C is described in Lovd as [Likely_pathogenic]. Variant chr2-47476435-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2074G>C	p.Gly692Arg	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.2074G>C	p.Gly692Arg	missense_variant	13/16	1	NM_000251.3	ENSP00000233146	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 02, 2020	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). Functional studies have shown that this variant disrupts DNA mismatch repair activity in yeast and mouse embryonic stem cell-based assays (PMID: 17720936, 26951660). This variant has been reported in individuals affected with Lynch syndrome-associated cancers (PMID: 10612836). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 20, 2017	The p.G692R pathogenic mutation (also known as c.2074G>C), located in coding exon 13 of the MSH2 gene, results from a G to C substitution at nucleotide position 2074. The glycine at codon 692 is replaced by arginine, an amino acid with dissimilar properties. In one study, this alteration was detected in the proband and two other affected members of a Portuguese Lynch/HNPCC syndrome family. The glycine at position 692 is in a well conserved region, close to the ATP binding domain (Isidro et al. Hum Mut. 2000 Jan; 15(1):116). Additionally, functional analysis of the yeast equivalent demonstrated 5% steady-state levels of 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 et al. Genetics. 2007 Oct; 177(2): 707-21). Another study looked at site-directed mutagenesis in mouse embryonic stem cells (mESCs) and selected for MMR-deficient cell lines which were subsequently sequenced to confirm that these cell lines contained the mutation of interest. The abundance of MSH2 protein in mESCs with the G692R alteration was 4% relative to the wildtype mESCs (MSH6 levels were also noted to mirror the decrease in MSH2 levels in the variant cell line); additionally, cells with the G692R alteration were shown to be MSI-H (Houlleberghs H et al. Proc. Natl. Acad. Sci. U.S.A. 2016 Apr;113:4128-33). This amino acid position is highly conserved in available vertebrate species. This alteration has been classified as likely pathogenic using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies (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 addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Lynch syndrome Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Jun 21, 2019

Multifactorial likelihood analysis posterior probability 0.95-0.99 -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 28, 2023

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: 90878). 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). 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). 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. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	32
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;D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	5.0	H;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.7	D;D;.;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;.;D
Polyphen		1.0	D;.;.;D
Vest4		0.99
MutPred		0.98		Loss of catalytic residue at C693 (P = 0.1643);.;Loss of catalytic residue at C693 (P = 0.1643);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

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: rs63750232; hg19: chr2-47703574;