Variant chr2-47403357-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3_Moderate

The NM_000251.3(MSH2):c.166G>A(p.Glu56Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000087 in 1,608,378 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E56Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000076 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:1

Conservation

PhyloP100: 6.03

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 4 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 13 benign, 17 uncertain in NM_000251.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.855

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.166G>A	p.Glu56Lys	missense_variant	1/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7 linkuse as main transcript	c.166G>A	p.Glu56Lys	missense_variant	1/16	1	NM_000251.3	P1	P43246-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152268

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000755

AC:

AN:

1456110

Hom.:

Cov.:

AF XY:

0.00000829

AC XY:

AN XY:

723928

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00

Gnomad4 NFE exome

AF:

0.00000900

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74394

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 16, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in proband with ovarian cancer; ClinVar: 1 VUS -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 13, 2023	This missense variant replaces glutamic acid with lysine at codon 56 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 ovarian cancer (PMID: 23047549) and an individual affected with colon cancer (PMID: 31997046). This variant has not been identified 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. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 16, 2021	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 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 16, 2023

- -

Lynch syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Oct 06, 2023

This missense variant replaces glutamic acid with lysine at codon 56 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 ovarian cancer (PMID: 23047549) and an individual affected with colon cancer (PMID: 31997046). This variant has not been identified 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

Oct 22, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in an individual with ovarian cancer and another with colorectal cancer whose tumor retained MSH2 expression on immunohistochemistry (PMID: 31997046, 23047549); Published functional studies demonstrate sensitivity to 6-thioguanine, suggesting intact mismatch repair function (PMID: 33357406); This variant is associated with the following publications: (PMID: 31997046, 23047549, 18822302, 21120944, 33357406) -

Hereditary nonpolyposis colorectal neoplasms

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 22, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 56 of the MSH2 protein (p.Glu56Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ovarian cancer and colorectal cancer (PMID: 23047549, 31997046). ClinVar contains an entry for this variant (Variation ID: 135854). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5436806:Mismatch repair cancer syndrome 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 02, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

D;.;.

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.86

D;D;D

MetaSVM

Uncertain

0.11

MutationAssessor

Uncertain

2.4

M;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-2.3

N;.;N

REVEL

Pathogenic

0.74

Sift

Benign

0.21

T;.;T

Sift4G

Benign

0.39

T;.;T

Polyphen

0.97

D;.;D

Vest4

0.88

MutPred

0.77

Gain of MoRF binding (P = 0.007);Gain of MoRF binding (P = 0.007);Gain of MoRF binding (P = 0.007);

MVP

0.99

MPC

0.023

ClinPred

0.99

GERP RS

2.5

Varity_R

0.65

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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