Submissions for variant NM_000179.3(MSH6):c.1805C>A (p.Ser602Ter)

dbSNP: rs730881816

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002230410	SCV000551120	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-07-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser602*) 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 colorectal cancer (PMID: 28528517). ClinVar contains an entry for this variant (Variation ID: 410441). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192458	SCV001360594	likely pathogenic	Hereditary nonpolyposis colon cancer	2019-04-16	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1805C>A (p.Ser602X) 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 (eg. c.2194C>T(p.Arg732X), c.2503C>T(p.Gln835X)). The variant was absent in 250434 control chromosomes (gnomAD) but has been reported in the literature in an individual affected with colon cancer (Morak_2017). Another variant with a different nucleotide change (c.1805C>G) but similar protein change has also been reported in the literature in an individual affected with renal/sarcoma/neuroectodermal tumor (Susswein_2015). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Revvity Omics, Revvity	RCV003139659	SCV003820200	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003449147	SCV004188322	pathogenic	Lynch syndrome 5	2023-08-15	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.