Variant 2-47482912-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000251.3(MSH2):c.2768T>A(p.Val923Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,611,726 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 6.75

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.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.89

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.2768T>A	p.Val923Glu	missense_variant	16/16	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.2768T>A	p.Val923Glu	missense_variant	16/16	1	NM_000251.3	ENSP00000233146	P1	P43246-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152198

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

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459528

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725848

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:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74358

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:

0.0000282

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 01, 2022	The p.V923E variant (also known as c.2768T>A), located in coding exon 16 of the MSH2 gene, results from a T to A substitution at nucleotide position 2768. The valine at codon 923 is replaced by glutamic acid, an amino acid with dissimilar properties. This variant has been reported in several Lynch syndrome families meeting Amsterdam criteria and/or suspected Lynch syndrome families (Bisgaard ML et al. Hum. Mutat., 2002 Jul;20:20-7; Ollila S et al. Gastroenterology, 2006 Nov;131:1408-17; Nilbert M et al. Fam. Cancer, 2009 Jun;8:75-83); however, this alteration has also been observed in an individual whose colorectal tumor demonstrated normal mismatch repair protein expression on immunohistochemistry (IHC) (Ambry internal data). This alteration demonstrated no reduction in mismatch repair capability compared to wildtype in vitro and caused mild reduction in mismatch binding and release capacity of MSH2 (Ollila S et al. Gastroenterology, 2006 Nov;131:1408-17; Ollila S et al. Hum. Mutat., 2008 Nov;29:1355-63). 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 deleterious (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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 23, 2022	This missense variant replaces valine with glutamic acid at codon 923 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). Experimental functional studies have provided inconsistent results for this variant (PMID 17101317, 18951462, 21431882, 33357406). This variant has been reported in individuals affected with Lynch Syndrome in the literature (PMID 12112654, 17101317, 18566915, 21431882). 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. -

Colorectal cancer, non-polyposis

Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Hereditary nonpolyposis colorectal neoplasms

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 17, 2023

This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 923 of the MSH2 protein (p.Val923Glu). This variant is present in population databases (rs146421227, gnomAD 0.0009%). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 12112654, 17101317, 18566915, 21431882). ClinVar contains an entry for this variant (Variation ID: 91043). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is expected to disrupt MSH2 function with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MSH2 function (PMID: 17101317, 18951462, 21431882, 33357406). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.77

D;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.86

D;D

M_CAP

Pathogenic

0.53

MetaRNN

Pathogenic

0.89

D;D

MetaSVM

Uncertain

0.74

MutationAssessor

Benign

2.0

M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-4.5

D;D

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0060

D;D

Polyphen

1.0

D;.

Vest4

0.74

MVP

0.98

MPC

0.025

ClinPred

0.99

GERP RS

5.4

Varity_R

0.95

gMVP

0.75

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