chr2-47429795-A-G

Position:

chr2-47429795-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6

The NM_000251.3(MSH2):c.1130A>G(p.Gln377Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:3

Conservation

PhyloP100: 8.44

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.

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 2-47429795-A-G is Benign according to our data. Variant chr2-47429795-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 237358.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=8}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.1130A>G	p.Gln377Arg	missense_variant	7/16	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.1130A>G	p.Gln377Arg	missense_variant	7/16	1	NM_000251.3	ENSP00000233146	P1	P43246-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251420

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135902

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461834

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727220

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Lynch syndrome 1

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 29, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 16, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 02, 2017	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 28, 2019	Variant summary: MSH2 c.1130A>G (p.Gln377Arg) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, core 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 4.1e-06 in 246238 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1130A>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 29, 2021	DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.1130A>G, in exon 7 that results in an amino acid change, p.Gln377Arg. This sequence change has been described in gnomAD with a frequency of 0.0029% in the Latino sub-population (dbSNP rs776174711). The p.Gln377Arg change affects a highly conserved amino acid residue located in a domain of the MSH2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Gln377Arg substitution. This sequence change does not appear to have been previously described in patients with MSH2-related disorders. Due to the lack of sufficient evidences, the clinical significance of the p.Gln377Arg change remains unknown at this time. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 31, 2022	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	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 03, 2023	This missense variant replaces glutamine with arginine at codon 377 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 suspected of having Lynch syndrome (Alvarez 2011 thesis, U. de Salamanca) and in individuals affected with breast/ovarian cancer (DOI: 10.1101/2021.04.15.21255554v2; Guardiola 2019 thesis, Univ. de Murcia; PMID: 33606809). This variant has been identified in 1/251420 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. -

Lynch syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Apr 27, 2023

This missense variant replaces glutamine with arginine at codon 377 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that cells expressing this variant responded normally to the anti-metabolite 6-thioguanine (PMID: 33357406). This variant has been reported in an individual suspected of having Lynch syndrome (Alvarez 2011 thesis, U. de Salamanca) and in individuals affected with breast/ovarian cancer (DOI: 10.1101/2021.04.15.21255554v2; Guardiola 2019 thesis, Univ. de Murcia; PMID: 33606809). This variant has been identified in 1/251420 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 27, 2024

Published functional studies demonstrate no damaging effect: exhibits sensitivity to 6-TG and mismatch repair (MMR) function similar to wild-type (PMID: 33357406); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35245693, 33357406, 36550560, 18822302, 21120944, 35264596, 33606809, 35534704) -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

- -

Hereditary cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.32

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

D;.;.;.

Eigen

Benign

0.11

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Uncertain

0.57

D;D;D;D

MetaSVM

Uncertain

-0.088

MutationAssessor

Benign

1.4

L;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-2.9

D;D;.;D

REVEL

Uncertain

0.59

Sift

Uncertain

0.0040

D;D;.;D

Sift4G

Benign

0.12

T;T;.;T

Polyphen

0.0010

B;.;.;B

Vest4

0.86

MutPred

0.42

Gain of MoRF binding (P = 0.054);.;Gain of MoRF binding (P = 0.054);Gain of MoRF binding (P = 0.054);

MVP

0.99

MPC

0.0067

ClinPred

0.58

GERP RS

5.6

Varity_R

0.88

gMVP

0.56

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