Submissions for variant NM_002439.5(MSH3):c.1644del (p.Gln549fs)

dbSNP: rs2112866857

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001963028	SCV002242563	pathogenic	not provided	2024-04-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln549Argfs*6) in the MSH3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH3 are known to be pathogenic (PMID: 27476653, 37402566). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH3-related conditions. ClinVar contains an entry for this variant (Variation ID: 1459256). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002388934	SCV002703766	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-12	criteria provided, single submitter	clinical testing	The c.1644delA pathogenic mutation, located in coding exon 11 of the MSH3 gene, results from a deletion of one nucleotide at nucleotide position 1644, causing a translational frameshift with a predicted alternate stop codon (p.Q549Rfs*6). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Myriad Genetics, Inc.	RCV003458803	SCV004189213	pathogenic	Familial adenomatous polyposis 4	2023-08-30	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
PreventionGenetics, part of Exact Sciences	RCV004731215	SCV005335897	pathogenic	MSH3-related disorder	2024-09-11	no assertion criteria provided	clinical testing	The MSH3 c.1644delA variant is predicted to result in a frameshift and premature protein termination (p.Gln549Argfs*6). To our knowledge, this variant has not been reported in the literature. This variant has not been reported in a large population database, indicating this variant is rare. This variant is classified as pathogenic by multiple submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/1459256/). Frameshift variants in MSH3 are expected to be pathogenic. This variant is interpreted as pathogenic.