Submissions for variant NM_000179.3(MSH6):c.3083C>G (p.Ser1028Ter)

dbSNP: rs876660853

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481140	SCV000571052	pathogenic	not provided	2016-07-25	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3083C>G at the cDNA level and p.Ser1028Ter (S1028X) at the protein level. The substitution creates a nonsense variant, which changes a Serine to a premature stop codon (TCA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in at least one individual with endometrial cancer (Le Gallo 2012) and is considered pathogenic.
Ambry Genetics	RCV000491967	SCV000580098	pathogenic	Hereditary cancer-predisposing syndrome	2025-03-07	criteria provided, single submitter	clinical testing	The p.S1028* pathogenic mutation (also known as c.3083C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 3083. This changes the amino acid from a serine to a stop codon within coding exon 4. This variant has been identified in a patient with MSH6 deficient ovarian cancer (Kim SR et al. Cancer, 2020 11;126:4886-4894). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	RCV000794243	SCV000933637	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-10-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser1028*) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with endometrial cancer (PMID: 23104009). ClinVar contains an entry for this variant (Variation ID: 421754). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV003449218	SCV004185624	pathogenic	Lynch syndrome 5	2023-08-22	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.