rs371614039

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BP4

The NM_000251.3(MSH2):c.1774A>G(p.Met592Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000824 in 1,613,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000086 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13B:3

Conservation

PhyloP100: 3.78

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 Uncertain_significance. Variant got 1 ACMG points.

PM1

In a helix (size 24) in uniprot entity MSH2_HUMAN there are 10 pathogenic changes around while only 2 benign (83%) in NM_000251.3

BP4

Computational evidence support a benign effect (MetaRNN=0.30504167).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3 link	c.1774A>G	p.Met592Val	missense_variant	12/16	ENST00000233146.7	NP_000242.1	P43246-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7 link	c.1774A>G	p.Met592Val	missense_variant	12/16	1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251442

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135892

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000855

AC:

125

AN:

1461502

Hom.:

Cov.:

AF XY:

0.0000839

AC XY:

AN XY:

727102

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.000107

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000108

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:13Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 18, 2021	The MSH2 c.1774A>G p.Met592Val variant (rs371614039) is reported in the literature in two individuals with a personal and family history of cancer (Nilbert 2009, Chubb 2015). This variant is also reported in ClinVar (Variation ID: 90782). The variant is found in the Non-Finnish European population with an allele frequency of 0.006% (8/129158 alleles) in the Genome Aggregation Database. The Methionine at codon 592 is moderately conserved and computational analyses predict that this variant is uncertain (REVEL: 0.383). Due to limited information, the clinical significance of the MSH2 c.1774A>G p.Met592Val variant is uncertain at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 11, 2024	The MSH2 c.1774A>G (p.Met592Val) variant has been reported in the published literature in individuals affected with Lynch syndrome (PMID: 18566915 (2009)), colorectal cancer (PMID: 25559809 (2015), 31391288 (2020), 32658311 (2021)), and breast cancer (PMID: 31569399 (2019), 32658311 (2021), 32986223 (2021), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MSH2)). This variant has also been reported in unaffected individuals (PMID: 32658311 (2021), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MSH2)). The frequency of this variant in the general population, 0.00062 (3/4824 chromosomes in Estonian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 2024	Observed in individuals with a personal and/or family history of colorectal or breast cancer, as well as in unaffected control groups (PMID: 18566915, 25559809, 31569399, 32658311, 32986223, 33471991); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26333163, 18383312, 18566915, 16995940, 25559809, 22290698, 23690608, 32986223, 32658311, 33471991, 31391288, 31569399, 18822302, 21120944, 9774676, 36243179) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	MSH2: PS3:Supporting -

not specified

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 23, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: 3VUS (including expert panel), no new evidence since expert classification -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 01, 2022	Variant summary: MSH2 c.1774A>G (p.Met592Val) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251442 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1774A>G has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer(example: Nilbert_2009, Drost_2013, Chubb_2015, Wu_2019, Ackay_2021, Banderia_2021 etc.). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrences with a pathogenic variant classified by our laboratory has been reported (BRCA1 c.5096G>A, p.R1699Q), providing supporting evidence for a benign role. In addition, a recent case-control study showed that this variant was not associated with breast cancer (Dorling_2021, LOVD database). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar classifying as VUS (n=9) and likely benign (n=1) Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Lynch syndrome 1

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 22, 2023	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 08, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 15, 2024	- -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 15, 2022	This missense variant replaces methionine with valine at codon 592 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in individuals affected with breast cancer (PMID: 31569399, 32658311, 32986223, 33471991), colorectal cancer (PMID: 25559809, 32658311), unspecified cancer (PMID: 31391288), and in a family affected with Lynch syndrome (PMID: 18566915). This variant has also been reported in numerous healthy individuals (PMID: 32658311, 33471991). This variant has been identified in 8/282822 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 15, 2018	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jul 16, 2021	- -

Lynch syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jun 09, 2024

This missense variant replaces methionine with valine at codon 592 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in individuals affected with breast cancer (PMID: 31569399, 32658311, 32986223, 33471991), colorectal cancer (PMID: 25559809, 32658311), unspecified cancer (PMID: 31391288), and in a family affected with Lynch syndrome (PMID: 18566915). This variant has also been reported in numerous healthy individuals (PMID: 32658311, 33471991). This variant has been identified in 8/282822 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The MSH2 p.Met592Val variant was identified in 3 of 3368 proband chromosomes (frequency: 0.0009) from individuals or families with Lynch syndrome or colorectal cancer (Chubb 2015, Nilbert 2009). The variant was also identified in dbSNP (ID: rs371614039) as "With other allele", ClinVar (classified as likely benign by Ambry Genetics; as uncertain significance by Invitae, GeneDx and four other submitters). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 8 of 277192 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 8 of 126706 chromosomes (freq: 0.00006), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Met592 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 12, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.068

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.49

T;.;.;.

Eigen

Benign

-0.093

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.93

D;D;D;D

M_CAP

Benign

0.053

MetaRNN

Benign

0.31

T;T;T;T

MetaSVM

Uncertain

-0.11

MutationAssessor

Benign

0.90

L;.;.;.

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.6

N;N;.;N

REVEL

Uncertain

0.38

Sift

Benign

0.23

T;T;.;T

Sift4G

Benign

0.20

T;T;.;T

Polyphen

0.0

B;.;.;B

Vest4

0.52

MVP

0.92

MPC

0.0070

ClinPred

0.48

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.55

gMVP

0.60

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