rs63751454

Positions:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. BS2BS3_SupportingPP3_ModerateBP5BS4_Supporting

This summary comes from the ClinGen Evidence Repository: The MSH2 c.913G>A variant is predicted as a missense variant, p.(Ala305Thr). Its MAPP+PolyPhen-2 prior probability for pathogenicity is >0.81 (http://priors.hci.utah.edu/PRIORS). It showed lack of co-segregation with disease with Bayes Likelihood Ratio >0.05 & ≤0.482 (Insight database). It was identified in 2 individuals with CRC showing MSS or inconsistent MMR protein expression pattern. It has been functionally analyzed in several studies: functional Odds for Pathogenicity is >0.05 & ≤0.482 (Drost et al., 2011 PMID 22102614); proficient function, expression and localization (PMID 18822302); proficient function (PMID 33357406). It has been identified in co-occurrence in trans with a MSH2 known pathogenic variant (Invitae internal data). Therefore, this variant is classified as likely benign. LINK:https://erepo.genome.network/evrepo/ui/classification/CA022539/MONDO:0005835/137

Frequency

Genomes: 𝑓 0.000077 ( 0 hom., cov: 27)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

11

7

1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:8

Conservation

PhyloP100: 7.72

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:

MSH2 (HGNC:):

MSH2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

BP5

For more information check the summary or visit ClinGen Evidence Repository.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

BS3

For more information check the summary or visit ClinGen Evidence Repository.

BS4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.913G>A	p.Ala305Thr	missense_variant	5/16	ENST00000233146.7	NP_000242.1	P43246-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7 linkuse as main transcript	c.913G>A	p.Ala305Thr	missense_variant	5/16	1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

AF:

0.0000768

AC:

9

AN:

117216

Hom.:

0

Cov.:

27

show subpopulations

Gnomad AFR

AF:

0.0000650

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:

0.000113

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000603

AC:

15

AN:

248830

Hom.:

0

AF XY:

0.0000595

AC XY:

8

AN XY:

134548

show subpopulations

Gnomad AFR exome

AF:

0.0000620

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:

0.000125

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000156

AC:

205

AN:

1315136

Hom.:

0

Cov.:

37

AF XY:

0.000142

AC XY:

93

AN XY:

655584

show subpopulations

Gnomad4 AFR exome

AF:

0.0000668

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:

0.000193

Gnomad4 OTH exome

AF:

0.000192

GnomAD4 genome

AF:

0.0000768

AC:

9

AN:

117216

Hom.:

0

Cov.:

27

AF XY:

0.0000749

AC XY:

4

AN XY:

53416

show subpopulations

Gnomad4 AFR

AF:

0.0000650

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:

0.000113

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000806

Hom.:

0

ESP6500AA

AF:

0.00

AC:

0

ESP6500EA

AF:

0.000116

AC:

1

ExAC

AF:

0.0000494

AC:

6

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 11, 2021	This variant is associated with the following publications: (PMID: 12419761, 22949379, 25637381, 9311737, 9709044, 18383312, 22102614, 27311873, 26333163, 19267393, 11048711, 18822302, 30998989, 21120944) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 08, 2024	The MSH2 c.913G>A (p.Ala305Thr) variant has been reported in the published literature in individuals affected with Lynch Syndrome (PMIDs: 9709044 (1998), 9311737 (1997)). Additionally, a functional study suggests that the variant is not damaging to protein function (PMIDs: 33357406 (2021), 22102614 (2012), 18822302 (2008)). The frequency of this variant in the general population, 0.00024 (10/41336 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 18, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 19, 2019	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 08, 2020	- -

not specified

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 15, 2022	Variant summary: MSH2 c.913G>A (p.Ala305Thr) results in a non-conservative amino acid change in 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 6e-05 in 249030 control chromosomes, predominantly at a frequency of 0.00012 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (6e-05 vs 0.00057), allowing no conclusion about variant significance. c.913G>A has been reported in the literature in individuals affected with colorectal cancer and/or undergoing panel-based genetic testing for Lynch syndrome/Hereditary Nonpolyposis Colorectal Cancer and in the NHLBI Exome Sequencing Project (ESP) cohort (example, Winjen_1997, Winjen_1998, Amendola_2015, Buchanan_2016, Dudley_2018, Kim_2020, Talbot_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch syndrome/Hereditary Nonpolyposis Colorectal Cancer. Several publications report experimental evidence evaluating an impact on protein function (example, Lutzen_2008, Drost_2011, Bouvet_2019, Jia_2021). The results of these studies showed no damaging effect of this variant in measures of MMR activity, no defect in nuclear localization, mismatch binding, ATP release, MSH6 binding and EXO1 binding. Nine submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. Five submitters classified the variant as likely benign, while four classified it as VUS. Based on the reproducible functional evidence as outlined above, and emerging consensus towards a benign outcome, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 05, 2020	DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.913G>A, in exon 5 that results in an amino acid change, p.Ala305Thr. This sequence change has been described in the gnomAD database with a low population frequency of 0.005% (dbSNP rs63751454). The p.Ala305Thr change affects a highly conserved amino acid residue located in a domain of the MSH2 protein that is known to be functional. The p.Ala305Thr substitution appears to be possibly damaging using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). The p.Ala305Thr variant has been reported in patients with Lynch syndrome (PMIDs: 9311737, 19267393), however functional studies performed have not provided evidence that the p.Ala305Thr variant leads to aberrant MSH2 expression, cellular localization or binding, or that this variant impacts mismatch repair activity (PMID: 22102614; Arnold et al., 2009). Due to these contrasting evidences, the clinical significance of the p.Ala305Thr change remains unknown at this time. -

Colorectal cancer, non-polyposis

Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Lynch syndrome

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The MSH2 p.Ala305Thr variant was identified in 1 of 368 proband chromosomes (frequency: 0.003) from Dutch individuals or families with HNPCC Lynch Syndrome and was not identified in 200 control chromosomes from healthy individuals (Wijnen 1997, Wijnen 1998). Lutzen et al (2008) used functional assays to show that the variant protein lacks any defect in mismatch binding, ATP-release, MMR activity, subcellular localization or protein-protein interactions. In an in vitro study looking at unclassified variants for possible splicing aberrations, tumours carrying the variant were found to have normal MMR activity, and lymphoblastoid cell line derived cDNA displayed normal wildtype product (Arnold 2009). An in silico model based on multivariate analysis predicted a MAPP-MMR score of 3.55, with anything >4.55 considered deleterious (Chao 2008); while an Australian study using a multifactorial likelihood model predicted the pathogenicity of the variant to be Class 3, (unclassified) (Thompson 2013). The variant was identified in dbSNP (ID: rs63751454) as â€šÃ„ÃºWith Uncertain significance alleleâ€šÃ„Ã¹, Clinvitae database (classification uncertain significance), â€šÃ„ÃºMismatch Repair Genes Variant Databaseâ€šÃ„Ã¹, â€šÃ„ÃºMMR Gene Unclassified Variants Databaseâ€šÃ„Ã¹, InSiGHT Colon Cancer Gene Variant Database- (LOVD) (11xX as Class 3), ClinVar database (classification uncertain significance, reviewed by an expert panel, submitters InSIGHT, GeneDx, Ambry Genetics, Invitae and CSER CC NCGL: University of Washington Medical Center), and UMD (1x with â€šÃ„Ã¹unclassified variantâ€šÃ„Ã¹ classification). This variant was also identified in the NHLBI GO Exome Sequencing Project in 1 of 8600 European American alleles (frequency: 0.0001), and in the Exome Aggregation Consortium database (August 8, 2016) in 6 of 121170 chromosomes (frequency: 0.00005) in the following populations: African in 1 of 10280 chromosomes (frequency: 0.0001) and European (Non-Finnish) in 5 of 66656 chromosomes (frequency: 0.00008), but was not seen in East Asian, European (Finnish), Latino, Other, or South Asian populations. The p.Ala305 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Breast and/or ovarian cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Apr 27, 2023

- -

MSH2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 23, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Pathogenic

0.32

D

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

28

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.77

D;.;.;.

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

D

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Pathogenic

0.30

D

MetaRNN

Pathogenic

0.89

D;D;D;D

MetaSVM

Pathogenic

0.95

D

MutationAssessor

Uncertain

2.9

M;.;.;.

PrimateAI

Uncertain

0.71

T

PROVEAN

Uncertain

-3.3

D;D;.;D

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0020

D;D;.;D

Sift4G

Uncertain

0.0040

D;D;.;D

Polyphen

1.0

D;.;.;D

Vest4

0.85

MVP

0.94

MPC

0.036

ClinPred

0.84

D

GERP RS

4.2

Varity_R

0.77

gMVP

0.40

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.

Other links and lift over

dbSNP: rs63751454; hg19: chr2-47641528; COSMIC: COSV51877627; COSMIC: COSV51877627;