Submissions for variant NM_000251.3(MSH2):c.1649_1650del (p.Lys550fs)

dbSNP: rs1114167835

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000490821	SCV000580505	pathogenic	Hereditary cancer-predisposing syndrome	2021-01-20	criteria provided, single submitter	clinical testing	The c.1649_1650delAA pathogenic mutation, located in coding exon 10 of the MSH2 gene, results from a deletion of two nucleotides at nucleotide positions 1649 to 1650, causing a translational frameshift with a predicted alternate stop codon (p.K550Ifs*11). This mutation was detected in a patient with endometrial cancer diagnosed before age 50 that showed high microsatellite instability (MSI-H), loss of MSH2 and MSH6 staining on immunohistochemistry (IHC) and who had a family history meeting Amsterdam criteria (Anagnostopoulos A et al. Int J Gynecol Cancer, 2017 06;27:931-937). 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	RCV001065122	SCV001230063	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-10-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys550Ilefs*11) 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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 428492). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV003449359	SCV004187947	pathogenic	Lynch syndrome 1	2023-08-02	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003478065	SCV004220954	likely pathogenic	not provided	2022-10-22	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the MSH2 mRNA and is predicted to cause the premature termination of MSH2 protein synthesis. The variant has not been reported in individuals with MSH2-related diseases in the published literature. It also has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as likely pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV004556791	SCV005045774	pathogenic	Lynch syndrome	2023-11-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004556791	SCV005429120	pathogenic	Lynch syndrome	2024-03-29	criteria provided, single submitter	clinical testing	The c.1649_1650del variant in the MSH2 gene is located in exon 10 and introduces a reading frameshift resulting in a premature translation termination codon (p.Lys550Ilefs*11). It is predicted to result in an absent or disrupted protein product. This variant has been reported in an individual diagnosed with Lynch syndrome (PMID: 28498244). ClinVar contains an entry for this variant (ID: 428492). This variant is absent in the general population database gnomAD. Truncating variants in MSH2 are known to be pathogenic (PMID: 15849733, 19419416). Therefore, this variant is classified as pathogenic.