2-47475171-G-C

Position:

chr2-47475171-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong

The ENST00000233146.7(MSH2):c.1906G>C(p.Ala636Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000743 in 1,613,998 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A636V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

MSH2
ENST00000233146.7 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:21O:1

Conservation

PhyloP100: 5.67

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 Likely_pathogenic. Variant got 8 ACMG points.

PP5

Variant 2-47475171-G-C is Pathogenic according to our data. Variant chr2-47475171-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 1764.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475171-G-C 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.1906G>C	p.Ala636Pro	missense_variant	12/16	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.1906G>C	p.Ala636Pro	missense_variant	12/16	1	NM_000251.3	ENSP00000233146	P1	P43246-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000864

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

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251462

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000191

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000864

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:

0.0000113

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:21Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 02, 2021	The variant has been reported in symptomatic individuals with colorectal, prostate, or endometrial cancer and in individuals affected with Constitutional Mismatch Repair Deficiency (CMMRD) syndrome (PMIDs: 12454801 (2002), 19101824 (2009), 21419771 (2011), 23990280 (2014), and 25117503 (2014)). In addition, functional studies have shown that this variant has a deleterious effect on MSH2 mismatch repair activity (PMIDs: 17101317 (2006), 18951462 (2008), 22102614 (2012), and 26951660 (2016)). This variant is a founder mutation in the Ashkenazi Jewish population (PMIDs: 12454801 (2002), 16199548 (2005), 21419771 (2011), and 22949379 (2013)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 31, 2021	PP1, PP5, PM3, PS3, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 30, 2022	Published functional studies demonstrate a damaging effect: reduced DNA repair efficiency and partial loss of function suggesting impact on MSH2 protein folding (Foulkes et al., 2002; Ollila et al., 2006; Drost et al., 2012; Houlleberghs et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22102614, 26951660, 25307252, 18674656, 28790115, 15845562, 16199548, 19267393, 18566915, 23990280, 25117503, 24362816, 22949387, 22949379, 21120944, 18951462, 17594722, 10528862, 17101317, 15516845, 26440929, 26544533, 27013479, 27601186, 27720647, 22045683, 22516243, 14668545, 28422960, 28526081, 28514183, 28510494, 12454801, 26681312, 28135145, 15872200, 20388775, 19101824, 18822302, 30572730, 29961768, 30152102, 29506128, 30702970, 30998989, 31857677, 31730237, 31491536, 31447099, 31615790, 32489267, 31948886, 30787465, 26556299, 33357406, 27535533, 25025451) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 29, 2016	- -
Pathogenic, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -

Lynch syndrome 1

Pathogenic:5Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Oct 15, 2018	The c.1906G>C (p.Ala636Pro) variant in the MSH2 gene has been reported in multiple Ashkenazi Jewish families affected with Lynch Syndrome (PMID 10528862, 12454801, 17101317,21419771) and segregates with disease in multiple families (PMID 10528862, 12454801). The overall hazardous ratio of developing colorectal cancer is 31.8 for men and 41.8 for women. The overall hazardous ratio of developing endometrial cancer is 66.7 (PMID 21419771) . Tumors from multiple index patients showed microsatellite instability with loss of MSH2 expression (PMID 12454801, 17101317). Functional studies suggest that this variant leads to DNA binding deficiency (PMID 18951462). Therefore, this c.1906G>C (p.Ala636Pro) variant in the MSH2 gene is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 10, 2015	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 21, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 24, 2023	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 10528862, 12454801]. -

Lynch syndrome

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 27, 2024	This missense variant replaces alanine with proline at codon 636 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant abolishes MMR activity in vitro (PMID: 17101317, 22102614), impacts MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold >= 0.88, PMID: 33357406), and causes deficient DNA binding (PMID: 18951462). This variant is known to be a founder mutation in Ashkenazi Jewish population and has been reported in up to 30% of families affected with Lynch syndrome (PMID: 12454801, 21419771, 23990280). This variant has also been observed in the homozygous state in individuals showing symptoms consistent with constitutional mismatch repair deficiency (PMID: 19101824, 23990280). Multifactorial analysis showed that the variant has a posterior probability of pathogenicity > 0.99 (PMID: 22949379). This variant has been identified in 5/282822 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 27, 2021	The p.Ala636Pro variant in MSH2 is a well-known founder variant, having been reported in many Ashkenazi Jewish individuals with Lynch syndrome and having been shown to segregate with disease in multiple families (Foulkes 2002 PMID: 12454801, Mukherjee 2011 PMID: 21419771, Dominguez-Valentin 2016 PMID: 27013479). Tumors from multiple index patients showed microsatellite instability with loss of MSH2 expression (Foulkes 2002 PMID 12454801, Ollila 2006 PMID:17101317). This variant has also been identified in 0.03% (3/10370) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). Multiple in vitro functional studies provide some evidence that this variant impacts protein function (Yuan 1999 PMID:10528862, Ollila 2006 PMID: 17101317, Houlleberghs 2016 PMID: 26951660). Additionally, this variant has also been observed in the homozygous state in individuals with symptoms consistent with constitutional mismatch repair deficiency (CMMRD). Moreover, this variant was classified as pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID: 1764). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PS4_Strong, PP1_Strong, PS3_Moderate, PM2_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Pathogenic, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	Abrogated function & CMMRD, >2 MSI-H tumours, co-segregation with disease & MAF 0.00. Multifactorial likelihood analysis posterior probability >0.99 -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Nov 25, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 11, 2021	The p.A636P pathogenic mutation (also known as c.1906G>C), located in coding exon 12 of the MSH2 gene, results from a G to C substitution at nucleotide position 1906. The alanine at codon 636 is replaced by proline, an amino acid with highly similar properties. This alteration represents an Ashkenazi Jewish founder mutation identified in numerous families meeting criteria for Lynch syndrome with supporting MSI/IHC tumor data (Yuan ZQ et al. J. Med. Genet. 1999 Oct;36:790-3; Foulkes WD et al. Am. J. Hum. Genet. 2002 Dec;71:1395-412; Sun S et al. J. Med. Genet. 2005 Oct;42:766-8; Goldberg Y et al. Fam. Cancer. 2014 Mar;13:65-73; Ambry Internal Data). It has also been identified in an individual with constitutional mismatch repair-deficiency (CMMR-D) syndrome who was homozygous for this alteration (Toledano H et al. Fam. Cancer. 2009;8:187-94). Functional assays and structural modeling indicate this alteration would have a deleterious impact on mismatch repair (Drost M et al. Hum. Mutat. 2012 Mar;33:488-94; Ollila S et al. Gastroenterology. 2006 Nov;131:1408-17; Jia X et al. Am J Hum Genet, 2021 01;108:163-175). This alteration has been classified as 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/]). Based on the available evidence, this alteration is classified as a pathogenic mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 03, 2023	This missense variant replaces alanine with proline at codon 636 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant abolishes MMR activity in vitro (PMID: 17101317, 22102614), impacts MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold >= 0.88, PMID: 33357406), and causes deficient DNA binding (PMID: 18951462). This variant is known to be a founder mutation in Ashkenazi Jewish population and has been reported in up to 30% of families affected with Lynch syndrome (PMID: 12454801, 21419771, 23990280). This variant has also been observed in the homozygous state in individuals showing symptoms consistent with constitutional mismatch repair deficiency (PMID: 19101824, 23990280). This variant has been identified in 5/282822 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Carcinoma of colon

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The MSH2 p.Ala636Pro variant was identified in 19 of 3058 proband chromosomes (frequency: 0.006) from individuals or families with colorectal, ovarian and endometrial cancers in Ashkenazi Jewish individuals, and was not identified in 3176 control chromosomes from healthy individuals. Functional studies showed that the addition of a single human chromosome containing the variant did not correct mismatch repair deficiency in MSH2 mouse cells confirming that this variant is a bona fide disease causing mutation. In addition, immunohistochemical data show that the protein is unstable (Foulkes 2002, Barak 2010, Durno 2005, Fidder 2005). The variant was also identified by our laboratory in 1 individual with ovarian cancer. The variant was further identified in dbSNP (ID: rs63750875) â€šÃ„ÃºWith Pathogenic Alleleâ€šÃ„Ã¹, in Exome Aggregation Consortium database (August 8, 2016) in 1 of 121410 chromosomes (freq. 000008) in the following population: 1 of 66740 chromosomes European (Non-Finnish) (freq. 0.00002); it was not seen in African, East Asian, European (Finnish), Latino populations and South Asian Populations. The variant was also identified in ClinVar and ClinVitae as pathogenic by Insight, Invitae, Ambry Genetics, GeneDx, LabCorp, OMIM and the Mayo Clinic Genetic Testing Laboratories; UMD 14X as Casual; InSiGHT Colon Cancer Gene Variant Database (LOVD), 52X as Class 5, and in MMR Gene Unclassified Variants Databases. The variant was not identified in the COGR, COSMIC, MutDB, Zhejiang Colon Cancer d(LOVD) databases or in the 1000 Genomes and NHLBI GO Exome Sequencing Projects. The p.Ala636 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. -

Hereditary nonpolyposis colorectal neoplasms

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 30, 2023

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 636 of the MSH2 protein (p.Ala636Pro). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with symptoms consistent with constitutional mismatch repair deficiency (PMID: 12454801, 19101824, 21419771, 23990280). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 12454801, 21419771, 23990280). ClinVar contains an entry for this variant (Variation ID: 1764). 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: 17101317, 18951462, 22102614). For these reasons, this variant has been classified as Pathogenic. -

Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5399763:Mismatch repair cancer syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.30

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

D;.;.;.

Eigen

Uncertain

0.67

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Benign

0.062

MetaRNN

Uncertain

0.60

D;D;D;D

MetaSVM

Uncertain

0.46

MutationAssessor

Uncertain

2.6

M;.;.;.

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.3

N;N;.;N

REVEL

Uncertain

0.64

Sift

Benign

0.066

T;T;.;T

Sift4G

Benign

0.15

T;T;.;T

Polyphen

0.48

P;.;.;P

Vest4

0.85

MVP

0.95

MPC

0.013

ClinPred

0.41

GERP RS

6.0

Varity_R

0.63

gMVP

0.88

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

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