Submissions for variant NM_000251.3(MSH2):c.2662del (p.Leu888fs)

dbSNP: rs63751007

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076537	SCV000107566	pathogenic	Lynch syndrome 1	2018-06-13	reviewed by expert panel	curation	codon 888 is cutoff for truncating variants in the last exon of MSH2
Ambry Genetics	RCV000491264	SCV000580557	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-05	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000629927	SCV000750883	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-10-10	criteria provided, single submitter	clinical testing	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). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). 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.
Myriad Genetics, Inc.	RCV000076537	SCV004187961	pathogenic	Lynch syndrome 1	2023-08-09	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357579	SCV001553087	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	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.