rs4987188

chr2-47416318-G-Achr2-47416318-G-Cchr2-47416318-G-T

Variant summary

Our verdict is Benign. Variant got -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:29 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

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 GnomAd at 22 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.965G>A	p.Gly322Asp	missense_variant	6/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.965G>A	p.Gly322Asp	missense_variant	6/16	1	NM_000251.3	P1

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

GnomAD3 exomes AF: 0.0134 AC: 3375 AN: 251428 Hom.: 48 AF XY: 0.0134 AC XY: 1817 AN XY: 135886

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

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.: 22 Cov.: 32 AF XY: 0.0132 AC XY: 981 AN XY: 74392

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.: 42

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:29 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:8 Other:1

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
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, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

Lynch syndrome 1 Benign:6

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Aug 07, 2015	- -
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	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	- -
Benign, no assertion criteria provided	clinical testing	Pathway Genomics	Jul 24, 2014	- -

Hereditary cancer-predisposing syndrome Benign:6

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

Lynch syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Nov 30, 2015	- -
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 -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 02, 2023	- -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -

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 (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

Benign, criteria provided, single submitter

clinical testing

Invitae

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	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;.;.;.
MutationTaster	Benign	1.0	D;D;D
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

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

Other links and lift over

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