rs3764959

chr2-47471169-A-Gchr2-47471169-A-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.1759+107A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.343 in 680,402 control chromosomes in the GnomAD database, including 45,949 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (15525 hom., cov: 32)
  • Exomes 𝑓: 0.32 (30424 hom.)
• Consequence: MSH2 NM_000251.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0160

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 2-47471169-A-G is Benign according to our data. Variant chr2-47471169-A-G is described in ClinVar as [Benign]. Clinvar id is 439907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47471169-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.667 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.1759+107A>G		intron_variant		ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.1759+107A>G		intron_variant		1	NM_000251.3	P1

Frequencies

GnomAD3 genomes AF: 0.414 AC: 62877 AN: 151936 Hom.: 15497 Cov.: 32

Gnomad AFR AF: 0.673

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.346

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.641

Gnomad SAS AF: 0.342

Gnomad FIN AF: 0.388

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.277

Gnomad OTH AF: 0.371

GnomAD4 exome AF: 0.322 AC: 170205 AN: 528348 Hom.: 30424 AF XY: 0.318 AC XY: 90410 AN XY: 284408

Gnomad4 AFR exome AF: 0.671

Gnomad4 AMR exome AF: 0.310

Gnomad4 ASJ exome AF: 0.233

Gnomad4 EAS exome AF: 0.593

Gnomad4 SAS exome AF: 0.320

Gnomad4 FIN exome AF: 0.386

Gnomad4 NFE exome AF: 0.274

Gnomad4 OTH exome AF: 0.341

GnomAD4 genome AF: 0.414 AC: 62957 AN: 152054 Hom.: 15525 Cov.: 32 AF XY: 0.416 AC XY: 30941 AN XY: 74324

Gnomad4 AFR AF: 0.674

Gnomad4 AMR AF: 0.346

Gnomad4 ASJ AF: 0.227

Gnomad4 EAS AF: 0.640

Gnomad4 SAS AF: 0.342

Gnomad4 FIN AF: 0.388

Gnomad4 NFE AF: 0.277

Gnomad4 OTH AF: 0.370

Alfa AF: 0.277 Hom.: 1215

Bravo AF: 0.421

Asia WGS AF: 0.496 AC: 1722 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 02, 2018	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 20, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.59
Dann	Benign	0.41

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: rs3764959; hg19: chr2-47698308;