rs63750466

Positions:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_000251.3(MSH2):c.4G>A(p.Ala2Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 1,595,188 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★★). Synonymous variant affecting the same amino acid position (i.e. A2A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:9B:12

Conservation

PhyloP100: 8.80

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 Benign. Variant got -8 ACMG points.

BP6

Variant 2-47403195-G-A is Benign according to our data. Variant chr2-47403195-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 41650.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47403195-G-A is described in Lovd as [Likely_benign]. Variant chr2-47403195-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.4G>A	p.Ala2Thr	missense_variant	1/16	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.4G>A	p.Ala2Thr	missense_variant	1/16	1	NM_000251.3	ENSP00000233146	P1	P43246-1

Frequencies

GnomAD3 genomes

AF:

0.0000722

AC:

AN:

152258

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:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000152

AC:

AN:

216606

Hom.:

AF XY:

0.000119

AC XY:

AN XY:

117838

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:

0.000391

Gnomad NFE exome

AF:

0.000259

Gnomad OTH exome

AF:

0.000185

GnomAD4 exome

AF:

0.000170

AC:

245

AN:

1442930

Hom.:

Cov.:

AF XY:

0.000173

AC XY:

124

AN XY:

716142

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.000357

Gnomad4 NFE exome

AF:

0.000197

Gnomad4 OTH exome

AF:

0.000151

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152258

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74390

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:

0.000188

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000193

Hom.:

Bravo

AF:

0.0000982

ExAC

AF:

0.000141

AC:

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:9Benign:12

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 06, 2018	The MSH2 c.4G>A; p.Ala2Thr variant (rs63750466) is reported in the literature in multiple individuals with Lynch syndrome (Kurzawski 2006, Mangold 2005a, Mangold 2005b, Nagasaka 2010, Pagenstecher 2006, Parc 2003). However, it has been reported to co-occur with a pathogenic MSH2 nonsense variant (Mangold 2005a) and a 3'EPCAM deletion where MSH2 promoter methylation was seen (Nagasaka 2010). This variant is also reported to co-segregate with disease in a large Lynch syndrome family where loss of the MSH2 protein was seen in four individual's tumors; however, RNA analysis showed normal expression, suggesting this variant may be a marker in this family but the functional consequences are uncertain (Pagenstecher 2006). This variant is considered uncertain by an expert review panel in ClinVar (Variation ID: 41650), and is found in the general population with an overall allele frequency of 0.01% (34/241756 alleles) in the Genome Aggregation Database. This variant occurs in a conserved nucleotide of the Kozak consensus sequence, but computational algorithms do not agree as to the effect this variant may have on the protein (SIFT: Tolerated, PolyPhen2: Probably Damaging). Based on available information, the clinical significance of p.Ala2Thr is uncertain at this time. REFERENCES Kurzawski G et al. Germline MSH2 and MLH1 mutational spectrum including large rearrangements in HNPCC families from Poland (update study). Clin Genet. 2006 Jan;69(1):40-7. Mangold E et al. Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer. Int J Cancer. 2005a Sep 20;116(5):692-702. Mangold E et al. Tumours from MSH2 mutation carriers show loss of MSH2 expression but many tumours from MLH1 mutation carriers exhibit weak positive MLH1 staining. J Pathol. 2005b Dec;207(4):385-95. Nagasaka T et al. Somatic hypermethylation of MSH2 is a frequent event in Lynch Syndrome colorectal cancers. Cancer Res. 2010 Apr 15;70(8):3098-108. Pagenstecher C et al. Aberrant splicing in MLH1 and MSH2 due to exonic and intronic variants. Hum Genet. 2006 Mar;119(1-2):9-22. Parc Y et al. Cancer risk in 348 French MSH2 or MLH1 gene carriers. J Med Genet. 2003 Mar;40(3):208-13. -
Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 09, 2021	- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Apr 09, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jun 11, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 24, 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. -

not specified

Uncertain:1Benign:2

Uncertain significance, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 03, 2019	Variant summary: MSH2 c.4G>A (p.Ala2Thr) 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. 5/5 computational tools predict no significant impact on normal splicing. This was confirmed by RT-PCR results (Pagenstecher_2006). The variant allele was found at a frequency of 0.00016 in 217422 control chromosomes (gnomAD and publication data). This frequency is not significantly higher than expected for a pathogenic variant in MSH2 causing Lynch Syndrome (0.00016 vs 0.00057), allowing no conclusion about variant significance. The variant, c.4G>A, has been reported in the literature in individuals affected with Lynch Syndrome, uveal malignant melanoma or autosomal dominant cancer predisposition syndromes (Mangold_2005, Kurzawski_2006, Schrader_2016, Bonadona_2011, Hajkova_2018, Zhang_2015). One publication reported one family where it showed segregation of this variant with Lynch syndrome (Mangold_2005). However, in many reports, not all MMR genes were tested or MLPA applied. Consequently, these reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Furthermore, in some of these families co-occurrences with other pathogenic variants have been reported (MSH2 c.1835C>G, p.Ser612X (Mangold_2005); EPCAM deletion associated with MSH2 promoter methylation (Nagasaka_2010); MSH2 c.1delA (UMD); RAD51C c.97C>T, p.Gln33X (Internal database)), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories and one expert panel (InSiGHT) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Likely benign (n=4 to include the expert panel), VUS (n=3)). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Lynch syndrome 1

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 24, 2023	This variant is considered benign. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease. 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	Jul 05, 2016	- -
Likely benign, reviewed by expert panel	curation	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Jun 13, 2018	Multifactorial likelihood analysis posterior probability < 0.05 (0.006) -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 08, 2021

- -

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.Ala2Thr variant was identified in 15 of 38724 proband chromosomes (frequency: 0.0004) from individuals or families with lynch syndrome or colorectal cancer (Bonadona 2011, Dymerska 2010, Johnston 2012, Kurzawski 2006, Mangold 2005, Nagasaka 2010, Parc 2003). The variant was identified in dbSNP (ID: rs63750466) as â€šÃ„ÃºWith Uncertain significance alleleâ€šÃ„Ã¹, ClinVar (as uncertain significance, reviewed by an expert panel including 6x as uncertain significance and 2x as likely benign), Clinvitae (5x), UMD-LSDB (30x as neutral), Mismatch Repair Genes Variant Database, and in the Insight Hereditary Tumors database (19x). In UMD the variant was identified with a co-occurring pathogenic MSH2 variant (c.1delA, p.Met1?), increasing the likelihood that the p.Ala2Thr variant does not have clinical significance. The variant was not identified in the COGR, Cosmic, MutDB, or Zhejiang University databases. The variant was identified in control databases in 34 of 241756 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: â€šÃ„ÃºOtherâ€šÃ„Ã¹ in 1 of 5740 chromosomes (freq: 0.0002), European in 25 of 109176 chromosomes (freq: 0.0002), and Finnish in 8 of 21430 chromosomes (freq: 0.0004); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, or South Asian populations. The p.Ala2 residue is conserved across mammals and other organisms, and four out of five 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 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In one study, Immunohistochemical analysis of this variant in tumors from relatives (mother and son - both of whom were carriers of the variant) revealed a loss of MSH2 protein expression; this finding supported a pathogenic role for the MSH2, c.4G>A, p.Ala2Thr variant (Mangold 2005). In another publication this variant is reported to segregate with the disease in several family members (at least 10 meioses) and showed loss of MSH2 expression in tumors of four affected family members. This variant is clearly linked to the disease in this specific family (Pagenstecher 2006). However, there is conflicting evidence in the literature; this variant was identified in an individual as co-occurring with pathogenic variant in MSH2 (c.1835C>G, p.S612X) (Lucci-Cordisco 2006, Mangold 2005). 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 carcinoma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

- -

MSH2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 28, 2021

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). -

Lynch syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

University of Washington Department of Laboratory Medicine, University of Washington

Feb 01, 2018

MSH2 p.A2T has been reported to co-occur with a MSH2 nonsense variant and a 3' EPCAM deletion where MSH2 promoter methylation was identified (Mangold 2005, Nagasaka 2010). Functional RNA studies performed on peripheral blood found normal RNA levels in patients that carry p.A2T (Pagenstecher 2006). MSH2 p.A2T was observed at an allele frequency of 0.0724% (14/19320 alleles) in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016), and it was observed in 1/208 individuals with atherosclerosis, with no specific information about cancer history (Johnston 2012). -

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

Pathogenic

0.75

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.43

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.41

T;.;.

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Pathogenic

0.53

MetaRNN

Uncertain

0.71

D;D;D

MetaSVM

Uncertain

0.72

MutationAssessor

Benign

1.8

L;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.6

N;.;N

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0030

D;.;D

Sift4G

Uncertain

0.011

D;.;T

Polyphen

1.0

D;.;D

Vest4

0.72

MVP

0.97

MPC

0.032

ClinPred

0.49

GERP RS

5.4

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.78

gMVP

0.63

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