2-47410167-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1

The NM_000251.3(MSH2):c.440T>G(p.Val147Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,614,012 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V147I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: 3.32

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 2 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 9 benign, 16 uncertain in NM_000251.3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.440T>G	p.Val147Gly	missense_variant	3/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7 linkuse as main transcript	c.440T>G	p.Val147Gly	missense_variant	3/16	1	NM_000251.3	P1	P43246-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152154

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251436

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727230

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74340

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000370

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 14, 2017	Variant summary: The c.440T>G (p.Val147Gly) in MSH2 gene is a missense change that involves a non-conserved nucleotide and 3/5 in silico tools predict deleterious outcome. The variant of interest is located outside of any known functional domain or repeats, however no studies determining the functional impact of this variant have been conducted and published at the time of evaluation. The variant is present in the large control population dataset of ExAC at a frequency 0.000016 (2/121412 chrs tested), which does not exceed the maximal expected frequency of a pathogenic allele (0.00057) in this gene. The variant is variant has been reported in 1 BrC patient without strong evidence for causality. The c.440T>G has not been cited by a reputable database/clinical laboratory. Taking together, the variant was classified as VUS. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 09, 2023	The MSH2 c.440T>G; p.Val147Gly variant (rs760851623) is reported in the literature in one individual affected with breast cancer (Tung 2016). This variant is also reported in ClinVar (Variation ID: 420893). This variant is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. A massively parallel cell based functional assay with susceptibility to DNA damaging agent, 6-thioguanine (6-TG), suggests the functionality of this variant to be neutral (Jia 2021). However, computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.645). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Jia X et al. Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk. Am J Hum Genet. 2021 Jan 7;108(1):163-175. PMID: 33357406. Tung N et al. Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer. J Clin Oncol. 2016 May 1;34(13):1460-8. PMID: 26976419. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2018	This variant is denoted MSH2 c.440T>G at the cDNA level, p.Val147Gly (V147G) at the protein level, and results in the change of a Valine to a Glycine (GTT>GGT). This variant was observed in a cohort of breast cancer patients, unselected for family history (Tung 2016). MSH2 Val147Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the connector domain (L?tzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Val147Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 27, 2023	This missense variant replaces valine with glycine at codon 147 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 an individual affected with breast cancer (PMID: 26976419). This variant has been identified in 2/251436 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 25, 2022	The p.V147G variant (also known as c.440T>G), located in coding exon 3 of the MSH2 gene, results from a T to G substitution at nucleotide position 440. The valine at codon 147 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been reported in a cohort of 488 patients with stages I to III breast cancer who were tested with a 25-gene panel test (Tung N et al. J Clin Oncol, 2016 May;34:1460-8). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 01;108:163-175). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

MSH2-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 16, 2023

The MSH2 c.440T>G variant is predicted to result in the amino acid substitution p.Val147Gly. This variant was reported as a variant of uncertain significance in a cohort of individuals with breast cancer (Table A2 in Tung et al 2016. PubMed ID: 26976419). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-47637306-T-G) and is reported in ClinVar as likely benign and uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/420893/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Lynch syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Aug 15, 2023

This missense variant replaces valine with glycine at codon 147 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 26976419). This variant has been identified in 2/251436 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. -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 23, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.18

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Pathogenic

0.85

D;T;.;.;.

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.14

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.61

T;T;T;T;T

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.64

D;D;D;D;D

MetaSVM

Uncertain

0.31

MutationAssessor

Uncertain

2.1

M;.;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.34

PROVEAN

Pathogenic

-5.8

D;D;D;.;D

REVEL

Pathogenic

0.65

Sift

Uncertain

0.022

D;D;D;.;D

Sift4G

Uncertain

0.019

D;D;D;.;D

Polyphen

0.0040

B;.;.;.;B

Vest4

0.45

MVP

0.97

MPC

0.0071

ClinPred

0.55

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.70

gMVP

0.89

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