Submissions for variant NM_002439.5(MSH3):c.47C>G (p.Ser16Ter)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003091448	SCV003475890	pathogenic	not provided	2024-04-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser16*) 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: 2162775). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV003367986	SCV004056889	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-10-03	criteria provided, single submitter	clinical testing	The p.S16* variant (also known as c.47C>G), located in coding exon 1 of the MSH3 gene, results from a C to G substitution at nucleotide position 47. This changes the amino acid from a serine to a stop codon within coding exon 1. The predicted stop codon occurs in the 5’ end of theMSH3 gene. Premature termination codons in the 5’ end of a gene have been reported to escape nonsense-mediated mRNAdecay and/or lead to re-initiation (Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653). Direct evidence for this alteration is unavailable, however premature termination codons are typically deleterious in nature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Myriad Genetics, Inc.	RCV003458896	SCV004189065	pathogenic	Familial adenomatous polyposis 4	2023-08-29	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.