Variant 2-47403411-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000233146.7(MSH2):c.211+9C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.432 in 1,587,578 control chromosomes in the GnomAD database, including 157,528 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.53 ( 23530 hom., cov: 34)

Exomes 𝑓: 0.42 ( 133998 hom. )

Consequence

MSH2
ENST00000233146.7 intron

Scores

Clinical Significance

Benign reviewed by expert panel B:22

Conservation

PhyloP100: -3.39

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 (BayesDel_noAF=-0.77).

BP6

Variant 2-47403411-C-G is Benign according to our data. Variant chr2-47403411-C-G is described in ClinVar as [Benign]. Clinvar id is 36573.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47403411-C-G is described in Lovd as [Benign]. Variant chr2-47403411-C-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.781 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.211+9C>G		intron_variant		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.211+9C>G		intron_variant		1	NM_000251.3	ENSP00000233146	P1	P43246-1

Frequencies

GnomAD3 genomes

AF:

0.530

AC:

80592

AN:

151992

Hom.:

23493

Cov.:

show subpopulations

Gnomad AFR

AF:

0.757

Gnomad AMI

AF:

0.343

Gnomad AMR

AF:

0.471

Gnomad ASJ

AF:

0.336

Gnomad EAS

AF:

0.803

Gnomad SAS

AF:

0.473

Gnomad FIN

AF:

0.576

Gnomad MID

AF:

0.335

Gnomad NFE

AF:

0.396

Gnomad OTH

AF:

0.488

GnomAD3 exomes

AF:

0.473

AC:

101041

AN:

213394

Hom.:

25877

AF XY:

0.462

AC XY:

54163

AN XY:

117226

show subpopulations

Gnomad AFR exome

AF:

0.766

Gnomad AMR exome

AF:

0.453

Gnomad ASJ exome

AF:

0.335

Gnomad EAS exome

AF:

0.815

Gnomad SAS exome

AF:

0.457

Gnomad FIN exome

AF:

0.575

Gnomad NFE exome

AF:

0.386

Gnomad OTH exome

AF:

0.423

GnomAD4 exome

AF:

0.421

AC:

604488

AN:

1435464

Hom.:

133998

Cov.:

AF XY:

0.420

AC XY:

298308

AN XY:

710378

show subpopulations

Gnomad4 AFR exome

AF:

0.768

Gnomad4 AMR exome

AF:

0.452

Gnomad4 ASJ exome

AF:

0.337

Gnomad4 EAS exome

AF:

0.775

Gnomad4 SAS exome

AF:

0.454

Gnomad4 FIN exome

AF:

0.570

Gnomad4 NFE exome

AF:

0.388

Gnomad4 OTH exome

AF:

0.450

GnomAD4 genome

AF:

0.530

AC:

80679

AN:

152114

Hom.:

23530

Cov.:

AF XY:

0.538

AC XY:

39972

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.757

Gnomad4 AMR

AF:

0.471

Gnomad4 ASJ

AF:

0.336

Gnomad4 EAS

AF:

0.802

Gnomad4 SAS

AF:

0.473

Gnomad4 FIN

AF:

0.576

Gnomad4 NFE

AF:

0.396

Gnomad4 OTH

AF:

0.486

Alfa

AF:

0.371

Hom.:

3171

Bravo

AF:

0.531

Asia WGS

AF:

0.637

AC:

2216

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:22

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 03, 2012	211+9C>G in intron 1 of MSH2: This variant is not expected to have clinical sign ificance because it is not located within the conserved +/- 1, 2 invariant regio n. It has been identified in 36% (3011/8418) of European American chromosomes fr om a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washi ngton.edu/EVS/; rs23033426). 211+9C>G in intron 1 of MSH2 (rs23033426; allele f requency= 36%, 3011/8418) ** -
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	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 27, 2015	- -

Lynch syndrome 1

Benign:5

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Illumina Laboratory Services, Illumina	Jan 13, 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. -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 30093976) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 19, 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	Color Diagnostics, LLC DBA Color Health	Dec 01, 2014	- -

Lynch syndrome

Benign:2

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

Carcinoma of colon

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The c.211+9C>G variant is not expected to have clinical significance because it is not located in the conserved region of the splicing consensus sequence. Furthermore, this variant is reported as a common polymorphism in dbSNP (rs2303426) and reported as a benign polymorphism in the literature. Average Heterozygosity: 0.488+/-0.075 -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.060

DANN

Benign

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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