Submissions for variant NM_000179.3(MSH6):c.3767_3771dup (p.Gln1258fs)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002510272	SCV002819283	likely pathogenic	Hereditary nonpolyposis colon cancer	2022-12-06	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3767_3771dupATTCT (p.Gln1258IlefsX9) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251198 control chromosomes. To our knowledge, no occurrence of c.3767_3771dupATTCT in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002569431	SCV003327677	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-04-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1258Ilefs*9) 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 variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 1878219). For these reasons, this variant has been classified as Pathogenic.