rs63750084

Positions:

• chr2-47482785-GA-G
• chr2-47482785-GA-GAA

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000251.3(MSH2):​c.2647del​(p.Ile883LeufsTer9) 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 (★★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSH2 NM_000251.3 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 8.08

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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-47482785-GA-G is Pathogenic according to our data. Variant chr2-47482785-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 91030.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47482785-GA-G is described in Lovd as [Pathogenic]. Variant chr2-47482785-GA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2647del	p.Ile883LeufsTer9	frameshift_variant	16/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.2647del	p.Ile883LeufsTer9	frameshift_variant	16/16	1	NM_000251.3	ENSP00000233146	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460988 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726804

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 1 Pathogenic:2

Pathogenic, reviewed by expert panel	curation	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Jun 13, 2018	This variant is before the cutoff (codon 888) and therefore Class 5 -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Aug 09, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 15, 2020	This variant deletes 1 nucleotide in exon 16 of the MSH2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 24, 2022	The c.2647delA pathogenic mutation, located in coding exon 16 of the MSH2 gene, results from a deletion of one nucleotide at nucleotide position 2647, causing a translational frameshift with a predicted alternate stop codon (p.I883Lfs*9). This alteration occurs at the 3' terminus of theMSH2 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 52 amino acids of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This mutation has been reported in multiple individuals and families with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome (Percesepe A et al. J. Clin. Oncol., 2001 Oct;19:3944-50; Bozzao C et al. Cancer, 2011 Sep;117:4325-35; Susswein LR et al. Genet Med, 2016 08;18:823-32; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Roberts ME et al. Genet Med, 2018 10;20:1167-1174). This variant has been identified in probands whose Lynch syndrome-associated tumors demonstrated high microsatellite instability and/or loss of MSH6 but retained MSH2 expression by immunohistochemistry (Hampel H et al. N Engl J Med, 2005 May;352:1851-60; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 23, 2020

Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with MSH2-related cancers (Percesepe 2001, Bozzao 2011, Susswein 2016); This variant is associated with the following publications: (PMID: 30322717, 11579115, 29025352, 21387278, 26681312, 14970868) -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 05, 2024

This sequence change creates a premature translational stop signal (p.Ile883Leufs*9) in the MSH2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 52 amino acid(s) of the MSH2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 11579115, 14970868, 30322717). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 91030). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Ile883 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9774676, 17531815, 18822302). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

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: rs63750084; hg19: chr2-47709924;