rs3732183

Positions:

• chr2-47466820-G-A
• chr2-47466820-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000251.3(MSH2):​c.1661+12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.307 in 1,606,350 control chromosomes in the GnomAD database, including 83,984 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.40 (14060 hom., cov: 32)
  • Exomes 𝑓: 0.30 (69924 hom.)
• Consequence: MSH2 NM_000251.3 intron
• Clinical Significance: Benign reviewed by expert panel B:20
• Conservation: PhyloP100: -0.868

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 (BayesDel_noAF=-0.85).
• BP6: Variant 2-47466820-G-A is Benign according to our data. Variant chr2-47466820-G-A is described in ClinVar as [Benign]. Clinvar id is 36567.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47466820-G-A is described in Lovd as [Benign]. Variant chr2-47466820-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.62 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.1661+12G>A		intron_variant		ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.1661+12G>A		intron_variant		1	NM_000251.3	P1

Frequencies

GnomAD3 genomes AF: 0.399 AC: 60625 AN: 151858 Hom.: 14041 Cov.: 32

Gnomad AFR AF: 0.623

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.340

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.640

Gnomad SAS AF: 0.342

Gnomad FIN AF: 0.388

Gnomad MID AF: 0.226

Gnomad NFE AF: 0.277

Gnomad OTH AF: 0.358

GnomAD3 exomes AF: 0.343 AC: 85978 AN: 250680 Hom.: 16803 AF XY: 0.334 AC XY: 45283 AN XY: 135652

Gnomad AFR exome AF: 0.628

Gnomad AMR exome AF: 0.295

Gnomad ASJ exome AF: 0.231

Gnomad EAS exome AF: 0.657

Gnomad SAS exome AF: 0.329

Gnomad FIN exome AF: 0.390

Gnomad NFE exome AF: 0.274

Gnomad OTH exome AF: 0.304

GnomAD4 exome AF: 0.298 AC: 433217 AN: 1454372 Hom.: 69924 Cov.: 32 AF XY: 0.297 AC XY: 215255 AN XY: 724012

Gnomad4 AFR exome AF: 0.630

Gnomad4 AMR exome AF: 0.300

Gnomad4 ASJ exome AF: 0.236

Gnomad4 EAS exome AF: 0.603

Gnomad4 SAS exome AF: 0.324

Gnomad4 FIN exome AF: 0.391

Gnomad4 NFE exome AF: 0.270

Gnomad4 OTH exome AF: 0.329

GnomAD4 genome AF: 0.399 AC: 60693 AN: 151978 Hom.: 14060 Cov.: 32 AF XY: 0.402 AC XY: 29850 AN XY: 74272

Gnomad4 AFR AF: 0.623

Gnomad4 AMR AF: 0.340

Gnomad4 ASJ AF: 0.227

Gnomad4 EAS AF: 0.639

Gnomad4 SAS AF: 0.342

Gnomad4 FIN AF: 0.388

Gnomad4 NFE AF: 0.277

Gnomad4 OTH AF: 0.357

Alfa AF: 0.301 Hom.: 3976

Bravo AF: 0.404

Asia WGS AF: 0.493 AC: 1713 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:20

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 17, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 03, 2012	1661+12G>A in intron 10 of MSH2: This variant is not expected to have clinical s ignificance because it is not located within the conserved +/- 1, 2 invariant re gion. It has been identified in >50% of African American chromosomes from a broa d population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu /EVS/; rs3732183). 1661+12G>A in intron 10 of MSH2 (rs3732183; allele frequency = >50%, 2637/4400) ** -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
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	PreventionGenetics, part of Exact Sciences	-	- -

Lynch syndrome 1 Benign:5

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	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Lynch syndrome Benign:2

Benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	MAF >1% -
Benign, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 29715107, 20931542, 11112663, 22283331, 24689082, 20305446) -

Hereditary cancer-predisposing syndrome Benign:2

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	Color Diagnostics, LLC DBA Color Health	Mar 30, 2015	- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Endometrial carcinoma Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The MSH2 c.1661+12G>A variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located within the consensus splice junction and is listed in dbSNP database as a common polymorphism (dbSNP ID: rs3732183). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.3
DANN	Benign	0.60

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: rs3732183; hg19: chr2-47693959; COSMIC: COSV99253307;