2-47414311-C-G

Position:

chr2-47414311-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3BP6

The NM_000251.3(MSH2):c.835C>G(p.Leu279Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,608,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000034 ( 0 hom., cov: 29)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:4

Conservation

PhyloP100: 3.20

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 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.748

BP6

Variant 2-47414311-C-G is Benign according to our data. Variant chr2-47414311-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135865.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=9}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.835C>G	p.Leu279Val	missense_variant	5/16	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.835C>G	p.Leu279Val	missense_variant	5/16	1	NM_000251.3	ENSP00000233146	P1	P43246-1

Frequencies

GnomAD3 genomes

AF:

0.0000335

AC:

AN:

149156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000246

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:

0.0000591

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000561

AC:

AN:

249628

Hom.:

AF XY:

0.0000742

AC XY:

AN XY:

134794

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:

0.0000462

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000149

AC:

218

AN:

1459652

Hom.:

Cov.:

AF XY:

0.000129

AC XY:

AN XY:

725928

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:

0.0000375

Gnomad4 NFE exome

AF:

0.000193

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000335

AC:

AN:

149156

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

72490

show subpopulations

Gnomad4 AFR

AF:

0.0000246

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:

0.0000591

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000112

Hom.:

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 26, 2022	Variant summary: MSH2 c.835C>G (p.Leu279Val) results in a conservative amino acid change located in the connector domain (IPR007860) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 249628 control chromosomes, predominantly at a frequency of 0.00011 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer/Lynch Syndrome (5.6e-05 vs 0.00057), allowing no conclusion about variant significance. c.835C>G has been reported in the literature in in individuals affected with colorectal cancer or other Lynch Syndrome-related cancers, including one individual who was also diagnosed with serrated polyposis syndrome and in an individual affected with breast cancer (e.g. Nilbert_2009, Limburg_2011, Tung_2014, Li_2020, Murphy_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch Syndrome. Co-occurrences with other pathogenic variants have been reported in the literature (BRCA2 c.5682C>A, p.Tyr1894X; Tung_2014) and UMD database (MLH1 c.117-1G>C), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. The majority classified the variant as VUS (n=7) and others classified the variant as likely benign (n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 21, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 18, 2019	- -

Lynch syndrome 1

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 20, 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, criteria provided, single submitter	clinical testing	Counsyl	May 31, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Jun 04, 2021	The MSH2 c.835C>G (p.Leu279Val) missense change has a maximum subpopulation frequency of 0.011% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/2-47641450-C-G). Six of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in at least one individual with colorectal cancer (PMID: 18566915, 21056691) and one individual with breast cancer (PMID: 26976419). It has also been reported in a non-cancer control subject (PMID: 29641532). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PP3. -

not provided

Uncertain:2Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2021	This variant is associated with the following publications: (PMID: 21056691, 18566915, 26976419, 27720647, 23729658) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 19, 2020	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	Feb 28, 2023	This missense variant replaces leucine with valine at codon 279 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 affected with rectal cancer and the tumor had detectable MSH2 by immunohistochemistry (PMID: 21056691), an individual affected with serrated polyposis syndrome and colorectal cancer (PMID: 35128723), and in a suspected Lynch syndrome family (PMID: 18566915). This variant also has been reported in an individual affected with breast cancer with a BRCA2 p.Tyr1894* covariant (PMID: 26976419), in two individuals affected with unspecified cancer (PMID: 31391288), and in a healthy control (PMID: 29641532). This variant has been identified in 15/280528 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

Jan 11, 2024

This missense variant replaces leucine with valine at codon 279 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 affected with rectal cancer and the tumor had detectable MSH2 by immunohistochemistry (PMID: 21056691), an individual affected with serrated polyposis syndrome and colorectal cancer (PMID: 35128723), and in a suspected Lynch syndrome family (PMID: 18566915). This variant also has been reported in an individual affected with breast cancer with a BRCA2 p.Tyr1894* covariant (PMID: 26976419), in two individuals affected with unspecified cancer (PMID: 31391288), and in a healthy control (PMID: 29641532). This variant has been identified in 15/280528 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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Uncertain

0.099

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

D;.;.;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.75

D;D;D;D

MetaSVM

Uncertain

0.52

MutationAssessor

Benign

1.6

L;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-2.3

N;N;.;N

REVEL

Uncertain

0.63

Sift

Benign

0.31

T;T;.;T

Sift4G

Benign

0.20

T;T;.;T

Polyphen

1.0

D;.;.;D

Vest4

0.74

MVP

0.88

MPC

0.019

ClinPred

0.56

GERP RS

5.1

Varity_R

0.65

gMVP

0.43

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