rs63750624

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000251.3(MSH2):c.484G>A(p.Gly162Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G162A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:13

Conservation

PhyloP100: 9.92

Publications

26 publications found

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 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

MSH2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 21 benign, 29 uncertain in NM_000251.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 2-47410211-G-A is Pathogenic according to our data. Variant chr2-47410211-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 91105.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3 link	c.484G>A	p.Gly162Arg	missense_variant	Exon 3 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7 link	c.484G>A	p.Gly162Arg	missense_variant	Exon 3 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251482

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Lynch syndrome 1

Pathogenic:3

Mar 22, 2023

Myriad Genetics, Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 18951462, 17101317, 18781619]. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 25085752]. -

Sep 17, 2020

Genetics and Molecular Pathology, SA Pathology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 28, 2017

Counsyl

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Feb 01, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.G162R pathogenic mutation (also known as c.484G>A), located in coding exon 3 of the MSH2 gene, results from a G to A substitution at nucleotide position 484. The glycine at codon 162 is replaced by arginine, an amino acid with dissimilar properties. This mutation has been seen in several individuals who met Amsterdam I/II or Bethesda criteria for HNPCC (Ollila S et al. Gastroenterology. 2006 Nov;131:1408-17; Belvederesi L et al. Hum. Mutat. 2008 Nov;29:E296-309; Rossi BM et al. BMC Cancer, 2017 Sep;17:623). 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 Jan;108:163-175). In addition, several other studies have shown this mutation to result in abnormal subcellular localization patterns, reduced MMR efficiency compared to the wild type, or was partially deleterious (Ollila S et al. Gastroenterology. 2006 Nov;131:1408-17; Kansikas M et al Hum. Mutat. 2011 Jan;32:107-15; Belvederesi L et al. Hum. Mutat. 2008 Nov;29:E296-309; Houlleberghs H et al. Proc. Natl. Acad. Sci. U.S.A., 2016 Apr;113:4128-33). Furthermore, 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. -

Jun 13, 2023

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces glycine with arginine at codon 162 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 has defects in mismatch repair activity, protein expression/stability and sub-cellular localization (PMID: 18781619, 18951462) and tolerance to DNA-damaging agents (PMID: 30998989, 33357406). This variant has been reported in individuals affected with Lynch syndrome and Lynch syndrome-associated cancers (PMID: 12537652, 17101317, 18781619, 34667028, 36356413). Several of these individuals had tumors displaying microsatellite instability and/or mismatch repair protein loss in MSH2 via immunohistochemistry. 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 Pathogenic. -

Nov 29, 2020

Sema4, Sema4

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Lynch syndrome

Pathogenic:2

Jul 06, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:research

Multifactorial likelihood analysis posterior probability >0.99 -

not provided

Pathogenic:2

Jul 31, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MSH2 c.484G>A (p.Gly162Arg) variant has been reported in the published literature in numerous individuals with Lynch/suspected Lynch syndrome (PMIDs: 34667028 (2022), 28874130 (2017), 28491141 (2017)), and Lynch syndrome-associated cancers (PMIDs: 36451132 (2022), 36356413 (2022), 29025352 (2018), 18781619 (2008), 12537652 (2002)). Experimental studies indicate this variant has deleterious effects on MSH2 protein stability and function (PMIDs: 18951462 (2008), 18781619 (2008), 17101317 (2006)). The frequency of this variant in the general population, 0.000004 (1/251482 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Jul 26, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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; Published functional studies demonstrate a damaging effect: decreased expression, increased MSI slippage, reduced mismatch repair capability, and partial failure of protein localization to the nucleus (PMID: 17101317, 18781619, 26951660); Identified in patients with a personal and/or family history of Lynch syndrome-related cancers, many meeting clinical criteria and/or with concordant tumor studies (PMID: 12537652, 18781619, 28874130, 29025352); This variant is associated with the following publications: (PMID: 21120944, 22949387, 31609810, 15991316, 22949379, 28874130, 30998989, 27606285, 17250665, 18383312, 18781619, 12537652, 24362816, 17101317, 17594722, 18951462, 26951660, 29625052, 28491141, 29025352, 18822302) -

Hereditary nonpolyposis colon cancer

Pathogenic:1

Oct 29, 2019

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MSH2 c.484G>A (p.Gly162Arg) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain (IPR007860) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251482 control chromosomes (gnomAD). c.484G>A has been reported in the literature in multiple individuals affected with colon cancer and HNPCC (Loader_2002, Ollila_2006, Belvederesi_2008, Thompson_2013, Brennan_2017, Rossi_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication, Ollila_2006, reports this variant had effects on protein stability, localization and DNA repair activity. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic -

Muir-Torré syndrome

Pathogenic:1

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense variant c.484G>Ap.Gly162Arg in MSH2 gene has been observed in heterozygous state in individuals with MSH2 related disorders Ponz et. al., 2018; Rossi et. al., 2017. Experimental studies have shown that this missense change affects MSH2 function Ollila et. al., 2008. The p.Gly162Arg variant is novel not in any individuals in 1000 Genomes and has allele frequency of 0.0004% in gnomAD exomes database. This variant has been reported to the ClinVar database as Pathogenic by mutiple submitters. The amino acid change p.Gly162Arg in MSH2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 162 is changed to a Arg changing protein sequence and it might alter its composition and physicochemical properties. For these reasons, this variant has been classified as Pathogenic. -

Hereditary nonpolyposis colorectal neoplasms

Pathogenic:1

Dec 20, 2024

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 162 of the MSH2 protein (p.Gly162Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with breast and prostate cancer, as well as individuals with clinicial features of Lynch syndrome (PMID: 12537652, 17101317, 18781619, 27606285, 28491141, 28874130, 29025352; internal data). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH2 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MSH2 testing. ClinVar contains an entry for this variant (Variation ID: 91105). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) 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, 18781619, 18951462, 22949387, 24362816, 30998989). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

D;D;.;.;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.99

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;D;D

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

M;.;.;.;.

PhyloP100

9.9

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-7.5

D;D;D;.;D

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;D;D;.;D

Sift4G

Pathogenic

0.0010

D;D;D;.;D

Polyphen

1.0

D;.;.;.;D

Vest4

0.99

MutPred

0.97

Gain of MoRF binding (P = 0.0369);.;.;Gain of MoRF binding (P = 0.0369);Gain of MoRF binding (P = 0.0369);

MVP

0.98

MPC

0.033

ClinPred

1.0

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

0.94

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over