chr2-47476408-G-A

Position:

chr2-47476408-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000251.3(MSH2):c.2047G>A(p.Gly683Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,068 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Pathogenic (★★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:8U:1

Conservation

PhyloP100: 9.60

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a helix (size 16) in uniprot entity MSH2_HUMAN there are 14 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, 0.98

PP5

Variant 2-47476408-G-A is Pathogenic according to our data. Variant chr2-47476408-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 90868.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47476408-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.2047G>A	p.Gly683Arg	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 linkuse as main transcript	c.2047G>A	p.Gly683Arg	missense_variant	13/16	1	NM_000251.3	ENSP00000233146	P1	P43246-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Lynch syndrome 1

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Aug 07, 2023	This variant is considered pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726]. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 11, 2024	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 21, 2020	In the published literature, the variant has been reported in multiple individuals with Lynch syndrome and MSH2-associated cancers (PMID: 11606497 (2001), 18931482 (2008), 19731080 (2010), 26248088 (2015)). A functional study showed the variant caused significantly reduced DNA mismatch repair activity and MSH2 protein expression in vitro (PMID: 23690608 (2013)). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant is located in a potentially critical protein domain. Therefore, the variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2024	Published functional studies demonstrate a damaging effect: increased mutation rate, impaired interaction with MSH6, and impaired mismatch repair (MMR) deficiency when compared to controls (PMID: 23690608, 28422960, 33357406); Observed in individuals with endometrial or colorectal cancer, with studied tumors demonstrating microsatellite instability (MSI) or absence of MSH2 expression on immunohistochemistry referred for genetic testing at GeneDx and in published literature (PMID: 11606497, 18931482, 20052760, 19731080, 26248088); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20052760, 18931482, 22290698, 23760103, 11606497, 26552419, 26248088, 24362816, 26078562, 19062740, 28422960, 25980754, 36550560, 27363726, 18383312, 19731080, 23690608, 31615790, 31830689, 18822302, 21120944, 33357406) -

Hereditary nonpolyposis colon cancer

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 15, 2020

Variant summary: MSH2 c.2047G>A (p.Gly683Arg) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251470 control chromosomes. c.2047G>A has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer (Sheng_2008, Samowitz_2001, Coolbaugh-Murphy_2010, Jasperson_2010). Experimental studies have shown the variant to result in deficient repair activity in in vitro MMR complementation assay (Drost_2013). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Lynch syndrome

Pathogenic:1

Pathogenic, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

Multifactorial likelihood analysis posterior probability >0.99 -

Hereditary nonpolyposis colorectal neoplasms

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 07, 2024

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 683 of the MSH2 protein (p.Gly683Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of MSH2-related conditions (PMID: 11606497, 18931482, 19731080, 26248088; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 90868). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MSH2 function (PMID: 23690608). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 13, 2021

The p.G683R pathogenic mutation (also known as c.2047G>A), located in coding exon 13 of the MSH2 gene, results from a G to A substitution at nucleotide position 2047. The glycine at codon 683 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been detected in multiple HNPCC/Lynch syndrome probands whose tumors demonstrated microsatellite instability (MSI-H) and/or absence of MSH2 staining on immunohistochemistry (IHC) (Samowitz WS et al. Gastroenterology 2001 Oct;121(4):830-8; Sheng JQ et al. Cytogenet. Genome Res. 2008 Oct;122:22-27; Jasperson KW et al. Fam. Cancer 2010 Jun;9:99-107; Ambry internal data). In vitro functional analysis of p.G683R showed a significant reduction in mismatch repair activity compared to wildtype MSH2 (Drost M et al. Proc. Natl. Acad. Sci. U.S.A. 2013 Jun;110:9403-8; Nielsen SV et al. PLoS Genet. 2017 Apr;13:e1006739). This alteration has been classified as definitely pathogenic (p>0.99) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, 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/]). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not specified

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Mayo Clinic Laboratories, Mayo Clinic

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

D;.;.;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D;D;D

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

0.88

MutationAssessor

Pathogenic

3.7

H;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-7.7

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

0.99

MutPred

0.89

Gain of MoRF binding (P = 0.0244);.;Gain of MoRF binding (P = 0.0244);Gain of MoRF binding (P = 0.0244);

MVP

0.97

MPC

0.033

ClinPred

1.0

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over