rs1981929

Positions:

• chr2-47445430-G-A
• chr2-47445430-G-C

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.1277-118G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.664 in 721,528 control chromosomes in the GnomAD database, including 162,971 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.72 (40716 hom., cov: 32)
  • Exomes 𝑓: 0.65 (122255 hom.)
• Consequence: MSH2 NM_000251.3 intron
• Clinical Significance: Benign reviewed by expert panel B:5
• Conservation: PhyloP100: 0.0930

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=-0.89).
• BP6: Variant 2-47445430-G-A is Benign according to our data. Variant chr2-47445430-G-A is described in ClinVar as [Benign]. Clinvar id is 90599.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47445430-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.9 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.1277-118G>A		intron_variant		ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1277-118G>A		intron_variant		1	NM_000251.3	ENSP00000233146	P1

Frequencies

GnomAD3 genomes AF: 0.719 AC: 109272 AN: 152016 Hom.: 40656 Cov.: 32

Gnomad AFR AF: 0.907

Gnomad AMI AF: 0.642

Gnomad AMR AF: 0.730

Gnomad ASJ AF: 0.578

Gnomad EAS AF: 0.854

Gnomad SAS AF: 0.706

Gnomad FIN AF: 0.708

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.603

Gnomad OTH AF: 0.691

GnomAD4 exome AF: 0.649 AC: 369473 AN: 569392 Hom.: 122255 AF XY: 0.648 AC XY: 197999 AN XY: 305614

Gnomad4 AFR exome AF: 0.907

Gnomad4 AMR exome AF: 0.787

Gnomad4 ASJ exome AF: 0.589

Gnomad4 EAS exome AF: 0.810

Gnomad4 SAS exome AF: 0.705

Gnomad4 FIN exome AF: 0.711

Gnomad4 NFE exome AF: 0.597

Gnomad4 OTH exome AF: 0.665

GnomAD4 genome AF: 0.719 AC: 109394 AN: 152136 Hom.: 40716 Cov.: 32 AF XY: 0.723 AC XY: 53767 AN XY: 74366

Gnomad4 AFR AF: 0.907

Gnomad4 AMR AF: 0.731

Gnomad4 ASJ AF: 0.578

Gnomad4 EAS AF: 0.853

Gnomad4 SAS AF: 0.705

Gnomad4 FIN AF: 0.708

Gnomad4 NFE AF: 0.603

Gnomad4 OTH AF: 0.691

Alfa AF: 0.606 Hom.: 35189

Bravo AF: 0.730

Asia WGS AF: 0.796 AC: 2761 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:2

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+	-	- -

not provided Benign:2

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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Lynch syndrome Benign:1

Benign, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

MAF >1% -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.62
DANN	Benign	0.37

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: rs1981929; hg19: chr2-47672569;