rs63751007

chr2-47482804-TC-T

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.2662del(p.Leu888CysfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. F887F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MSH2 NM_000251.3 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 0.328

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 13 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-47482804-TC-T is Pathogenic according to our data. Variant chr2-47482804-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 91035.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47482804-TC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.2662del	p.Leu888CysfsTer4	frameshift_variant	16/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.2662del	p.Leu888CysfsTer4	frameshift_variant	16/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 1 Pathogenic:2

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. -
Pathogenic, reviewed by expert panel	curation	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Jun 13, 2018	codon 888 is cutoff for truncating variants in the last exon of MSH2 -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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The MSH2 p.Leu888CysfsX4 variant was identified in 3 of 28 proband chromosomes (frequency: 0.107142857142857) from individuals or families with colorectal cancer (Swensen 1997 9222765). The variant was also identified in the following databases: dbSNP (ID: rs63751007) as “With Pathogenic allele”, ClinVar (2x with conflicting prediction of pathogenicity, as uncertain significance by Insight and as pathogenic by Ambry Genetics), UMD-LSDB (7x, as causal), Insight Hereditary Tumors Database (4x as "disruptive variant”). The variant was not identified in Cosmic, MutDB, Zhejiang Colon Cancer Database and Mismatch Repair Genes Variant Database. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.2662del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 888 and leads to a premature stop codon 4 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MSH2 gene are an established mechanism of disease in colorectal cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 10, 2023

This sequence change creates a premature translational stop signal (p.Leu888Cysfs*4) in the MSH2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 47 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 colorectal cancer (PMID: 8640829, 9222765, 21879275). It has also been observed to segregate with disease in related individuals. This variant is also known as codon 888delC and c.2662del. ClinVar contains an entry for this variant (Variation ID: 91035). 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 MSH6 and MSH3 interaction domains of the MSH2 protein, as well as the helix-turn-helix domain, which are important for proper dimerization and normal protein functioning (PMID: 9774676, 18822302, 17531815). While functional studies have not been performed to directly test the effect of this variant on MSH2 protein function, this suggests that disruption of this region of the protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 05, 2022

The c.2662delC pathogenic mutation, located in coding exon 16 of the MSH2 gene, results from a deletion of one nucleotide at nucleotide position 2662, causing a translational frameshift with a predicted alternate stop codon (p.L888Cfs*4). This mutation has been reported in one family that met Amsterdam Criteria (Swensen J et al. Hum Mutat. 1997;10(1):80-1). 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: rs63751007; hg19: chr2-47709943;