rs4987188

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000251.3(MSH2):c.965G>A(p.Gly322Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0145 in 1,612,018 control chromosomes in the GnomAD database, including 240 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.012 ( 22 hom., cov: 32)

Exomes 𝑓: 0.015 ( 218 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:30O:1

Conservation

PhyloP100: 4.65

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009123743).

BP6

Variant 2-47416318-G-A is Benign according to our data. Variant chr2-47416318-G-A is described in ClinVar as [Benign]. Clinvar id is 1762.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47416318-G-A is described in Lovd as [Benign]. Variant chr2-47416318-G-A is described in Lovd as [Likely_benign]. Variant chr2-47416318-G-A is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0124 (1885/152188) while in subpopulation NFE AF= 0.0173 (1175/68008). AF 95% confidence interval is 0.0165. There are 22 homozygotes in gnomad4. There are 981 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 22 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.965G>A	p.Gly322Asp	missense_variant	6/16	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.965G>A	p.Gly322Asp	missense_variant	6/16	1	NM_000251.3	ENSP00000233146	P1	P43246-1

Frequencies

GnomAD3 genomes

AF:

0.0124

AC:

1889

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00229

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.00787

Gnomad ASJ

AF:

0.0196

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00769

Gnomad FIN

AF:

0.0319

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0173

Gnomad OTH

AF:

0.0134

GnomAD3 exomes

AF:

0.0134

AC:

3375

AN:

251428

Hom.:

AF XY:

0.0134

AC XY:

1817

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.00209

Gnomad AMR exome

AF:

0.00598

Gnomad ASJ exome

AF:

0.0220

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00692

Gnomad FIN exome

AF:

0.0310

Gnomad NFE exome

AF:

0.0171

Gnomad OTH exome

AF:

0.0145

GnomAD4 exome

AF:

0.0147

AC:

21504

AN:

1459830

Hom.:

218

Cov.:

AF XY:

0.0146

AC XY:

10590

AN XY:

726418

show subpopulations

Gnomad4 AFR exome

AF:

0.00203

Gnomad4 AMR exome

AF:

0.00615

Gnomad4 ASJ exome

AF:

0.0219

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00664

Gnomad4 FIN exome

AF:

0.0295

Gnomad4 NFE exome

AF:

0.0158

Gnomad4 OTH exome

AF:

0.0135

GnomAD4 genome

AF:

0.0124

AC:

1885

AN:

152188

Hom.:

Cov.:

AF XY:

0.0132

AC XY:

981

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.00229

Gnomad4 AMR

AF:

0.00786

Gnomad4 ASJ

AF:

0.0196

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00769

Gnomad4 FIN

AF:

0.0319

Gnomad4 NFE

AF:

0.0173

Gnomad4 OTH

AF:

0.0133

Alfa

AF:

0.0151

Hom.:

Bravo

AF:

0.00931

TwinsUK

AF:

0.0148

AC:

ALSPAC

AF:

0.0156

AC:

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.0153

AC:

132

ExAC

AF:

0.0141

AC:

1709

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0162

EpiControl

AF:

0.0140

ClinVar

Significance: Benign

Submissions summary: Benign:30Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:8Other:1

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Lynch syndrome 1

Benign:6

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Aug 07, 2015	- -
Benign, no assertion criteria provided	clinical testing	Pathway Genomics	Jul 24, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Hereditary cancer-predisposing syndrome

Benign:6

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 01, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Dec 18, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	This alteration is classified as 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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 30, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Aug 18, 2022	- -
Benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Dec 01, 2017	- -

Lynch syndrome

Benign:3

Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 08, 2015	- -
Benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	MAF >1% & Multifactorial likelihood analysis posterior probability <0.001 -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Nov 30, 2015	- -

not provided

Benign:3

Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 02, 2023	- -

Carcinoma of colon

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The p.Gly322Asp variant has been identified in 78 out of 3532 proband chromosomes (frequency 0.022) in individuals with endometrial and colorectal cancer phenotypes, however it is also found in 69 out of 2790 control chromosomes (frequency 0.025), increasing the likelihood that this is a benign variant (Barneston 2008, Christensen 2008, Aceto 2009, Hampel 2006, Kurzawski 2006, Raptis 2005, Valentin 2011, Pastrello 2011, Sven Arnold_2009). It is listed in dbSNP database (ID#: rs4987188) with an average heterozygosity of 0.019+/-0.096 in various human populations, further suggesting the benign nature of this variant. The p.Gly322 is highly conserved in mammals and other species, however in silico computational analysis (Sift, PolyPhen and AlignGVGD) do not suggest an impact on the protein function, therefore increasing the likelihood of this variant to be benign. Although functional impact for the yeast homolog (yMSH2â€šÃ„Ã¬G317D) have been suggeested by earlier yeast assays (Drotschmann 1999; Ellison 2001), recent studies did not implicate any functional impact associated with the p.Gly322Asp variant (Wielders 2011, Kansikas 2011, Ollila 2008). In summary, based on the above information this variant is classified as Benign. -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

MSH2 POLYMORPHISM

Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Nov 01, 1998

- -

Breast carcinoma

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.067

BayesDel_noAF

Pathogenic

0.15

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.42

T;.;.;.

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

D;D;D;D

MetaRNN

Benign

0.0091

T;T;T;T

MetaSVM

Uncertain

0.093

MutationAssessor

Uncertain

2.2

M;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-2.0

N;N;.;N

REVEL

Uncertain

0.56

Sift

Benign

0.13

T;T;.;T

Sift4G

Benign

0.25

T;T;.;T

Polyphen

0.43

B;.;.;P

Vest4

0.18

MPC

0.0063

ClinPred

0.016

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.26

gMVP

0.34

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