rs63750682

Positions:

• chr2-47410312-AC-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000251.3(MSH2):​c.587del​(p.Pro196GlnfsTer18) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MSH2 NM_000251.3 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 7.84

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-47410312-AC-A is Pathogenic according to our data. Variant chr2-47410312-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 91142.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47410312-AC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.587del	p.Pro196GlnfsTer18	frameshift_variant	3/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.587del	p.Pro196GlnfsTer18	frameshift_variant	3/16	1	NM_000251.3	ENSP00000233146	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jul 27, 2023

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Lynch syndrome Pathogenic:1

Pathogenic, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

Coding sequence variation resulting in a stop codon -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 29, 2022

This premature translational stop signal has been observed in individual(s) with MSH2-related conditions (PMID: 15872200). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 91142). This variant is also known as c.586delC. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Pro196Glnfs*18) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2022

The c.587delC pathogenic mutation, located in coding exon 3 of the MSH2 gene, results from a deletion of one nucleotide at nucleotide position 587, causing a translational frameshift with a predicted alternate stop codon (p.P196Qfs*18). This pathogenic mutation has been reported in individuals with clinical histories consistent with Lynch syndrome and Muir-Torre syndrome (Hampel H et al. N. Engl. J. Med. 2005 May; 352(18):1851-60; South CD et al. J. Natl. Cancer Inst. 2008 Feb; 100(4):277-81). Of note, this alteration is also designated as c.586delC in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

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: rs63750682; hg19: chr2-47637451;