rs4987188

Variant names:

• chr2-47416318-G-A
• rs4987188
• NM_000251.3:c.965G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-47416318-G-A
• chr2-47416318-G-C
• chr2-47416318-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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 (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G322S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.012 (22 hom., cov: 32)
  • Exomes 𝑓: 0.015 (218 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Benign reviewed by expert panel B:31 O:1
• Conservation: PhyloP100: 4.65

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]

ACMG classification

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.965G>A	p.Gly322Asp	missense_variant	Exon 6 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.965G>A	p.Gly322Asp	missense_variant	Exon 6 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1889 AN: 152070 Hom.: 22 Cov.: 32

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

GnomAD2 exomes AF: 0.0134 AC: 3375 AN: 251428 AF XY: 0.0134

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 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.: 29 AF XY: 0.0146 AC XY: 10590 AN XY: 726418

Gnomad4 AFR exome AF: 0.00203 AC: 68 AN: 33446

Gnomad4 AMR exome AF: 0.00615 AC: 275 AN: 44724

Gnomad4 ASJ exome AF: 0.0219 AC: 573 AN: 26116

Gnomad4 EAS exome AF: 0.0000504 AC: 2 AN: 39672

Gnomad4 SAS exome AF: 0.00664 AC: 572 AN: 86206

Gnomad4 FIN exome AF: 0.0295 AC: 1573 AN: 53412

Gnomad4 NFE exome AF: 0.0158 AC: 17579 AN: 1110142

Gnomad4 Remaining exome AF: 0.0135 AC: 813 AN: 60344

GnomAD4 genome AF: 0.0124 AC: 1885 AN: 152188 Hom.: 22 Cov.: 32 AF XY: 0.0132 AC XY: 981 AN XY: 74392

Gnomad4 AFR AF: 0.00229 AC: 0.00228695 AN: 0.00228695

Gnomad4 AMR AF: 0.00786 AC: 0.00785649 AN: 0.00785649

Gnomad4 ASJ AF: 0.0196 AC: 0.0195965 AN: 0.0195965

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00769 AC: 0.00769231 AN: 0.00769231

Gnomad4 FIN AF: 0.0319 AC: 0.0319169 AN: 0.0319169

Gnomad4 NFE AF: 0.0173 AC: 0.0172774 AN: 0.0172774

Gnomad4 OTH AF: 0.0133 AC: 0.0132953 AN: 0.0132953

Alfa AF: 0.0145 Hom.: 85

Bravo AF: 0.00931

TwinsUK AF: 0.0148 AC: 55

ALSPAC AF: 0.0156 AC: 60

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.0153 AC: 132

ExAC AF: 0.0141 AC: 1709

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0162

EpiControl AF: 0.0140

ClinVar

Significance: Benign

Submissions summary: Benign:31 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:8 Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Sep 27, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Lynch syndrome 1 Benign:7

Jul 28, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 24, 2014

Pathway Genomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 07, 2015

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 05, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hereditary cancer-predisposing syndrome Benign:6

Nov 18, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 01, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 18, 2022

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2017

True Health Diagnostics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 18, 2015

Vantari Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Lynch syndrome Benign:3

Apr 08, 2015

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 30, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: research

MAF >1% & Multifactorial likelihood analysis posterior probability <0.001 -

not provided Benign:3

Nov 02, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Carcinoma of colon Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 (yMSH2–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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MSH2 POLYMORPHISM Benign:1

Nov 01, 1998

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Breast carcinoma Benign:1

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;.;.;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D;D;D;D
MetaRNN	Benign	0.0091	T;T;T;T
MetaSVM	Uncertain	0.093	D
MutationAssessor	Uncertain	2.2	M;.;.;.
PrimateAI	Uncertain	0.56	T
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	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.26
gMVP		0.34
Mutation Taster		=84/16	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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

Other links and lift over

dbSNP: rs4987188; hg19: chr2-47643457; COSMIC: COSV51880340;