rs549467183

Positions:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1BP4_StrongBP6_Strong

The NM_000251.3(MSH2):c.1963G>A(p.Val655Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000379 in 1,611,410 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 1 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:4B:8

Conservation

PhyloP100: 1.40

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_benign. Variant got -6 ACMG points.

PM1

In a region_of_interest Interaction with EXO1 (size 70) in uniprot entity MSH2_HUMAN there are 24 pathogenic changes around while only 4 benign (86%) in NM_000251.3

BP4

Computational evidence support a benign effect (MetaRNN=0.04226145).

BP6

Variant 2-47475228-G-A is Benign according to our data. Variant chr2-47475228-G-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 127637.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=3, Uncertain_significance=4}. Variant chr2-47475228-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.1963G>A	p.Val655Ile	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.1963G>A	p.Val655Ile	missense_variant	12/16	1	NM_000251.3	ENSP00000233146	P1	P43246-1

Frequencies

GnomAD3 genomes

AF:

0.0000397

AC:

AN:

151208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000264

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000417

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000131

AC:

AN:

251324

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000752

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000377

AC:

AN:

1460122

Hom.:

Cov.:

AF XY:

0.0000372

AC XY:

AN XY:

726324

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000694

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000397

AC:

AN:

151288

Hom.:

Cov.:

AF XY:

0.0000406

AC XY:

AN XY:

73832

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000264

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000418

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000529

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4Benign:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Lynch syndrome 1

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Jan 04, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 21, 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, reviewed by expert panel	curation	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Jun 13, 2018	MLH1 methylation, but tumour with all proteins absent by IHC, proficient in CIMRA -

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2021	This variant is associated with the following publications: (PMID: 26845104, 28767289, 25186627, 30212499, 30262796, 33294277, 32659497, 31569399) -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	May 10, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 06, 2022	- -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 14, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 23, 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. -

Lynch syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

University of Washington Department of Laboratory Medicine, University of Washington

Nov 20, 2015

- -

Mismatch repair cancer syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Jul 09, 2020

The homozygous p.Val655Ile missense variant identified in MSH2 has been reported in the literature in individuals affected with pancreatic ductal adenocarcinoma [PMID: 28767289] and breast and ovarian cancer syndrome [PMID: 30262796]. The variant has been reported in ClinVar by multiple independent sources with conflicting interpretations about its pathogenicity [classified as benign, likely benign, and a variant of uncertain significance. Variation ID: 127637]. The p.Val655Ile variant is classified as a variant of uncertain significance by the ClinVar/ClinGen expert panel [Variation ID:127637]. The variant has 0.00003510 allele frequency in the gnomAD(v3) database (5 out of 142,452 heterozygous alleles), and 0.0001313 allele frequency in the “Exome subset” of gnomAD(v2) database (33 out of 251,324 heterozygous alleles, 1 homozygote). The affected residue is not well conserved. In Silico prediction tools provide conflicting interpretations about potential pathogenicity of this variant. Based on the current evidence, the p.Val655Ile variant in the MSH2 gene is assessed as a variant of uncertain significance. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

May 12, 2022

Variant summary: MSH2 c.1963G>A (p.Val655Ile) results in a conservative amino acid change in 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 0.00013 in 251324 control chromosomes, predominantly at a frequency of 0.00075 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is higher than the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Lynch Syndrome phenotype (0.00057), suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.1963G>A has been reported in the literature in sequencing studies among individuals affected with breast, colorectal and pancreatic cancers (example, Shirts_2016, Tung_2015, Shindo_2017). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s) have been reported in the literature and at our laboratory (BRCA1 del exons 9-12, Tung_2015; ATM c.8264_8268delATAAG, p.Tyr2755fs*12, Internal testing data), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten 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. Multiple submitters have reported the variant with conflicting assessments (6 as benign/likely benign and 4 as a VUS). Based on the evidence outlined above, the variant was classified as benign. -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.39

T;.;.;.

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.63

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.82

T;T;T;T

M_CAP

Benign

0.022

MetaRNN

Benign

0.042

T;T;T;T

MetaSVM

Benign

-0.56

MutationAssessor

Benign

0.66

N;.;.;.

MutationTaster

Benign

0.99

D;D;D

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.46

N;N;.;N

REVEL

Uncertain

0.36

Sift

Benign

0.25

T;T;.;T

Sift4G

Benign

0.41

T;T;.;T

Polyphen

0.028

B;.;.;B

Vest4

0.45

MutPred

0.57

Loss of phosphorylation at Y656 (P = 0.1133);.;Loss of phosphorylation at Y656 (P = 0.1133);Loss of phosphorylation at Y656 (P = 0.1133);

MVP

0.79

MPC

0.0075

ClinPred

0.025

GERP RS

2.8

Varity_R

0.039

gMVP

0.39

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