Submissions for variant NM_000179.3(MSH6):c.458-5del

dbSNP: rs587781955

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130330	SCV000185180	likely benign	Hereditary cancer-predisposing syndrome	2014-01-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000200208	SCV000253117	likely benign	Lynch syndrome	2015-06-03	criteria provided, single submitter	clinical testing
Invitae	RCV000532572	SCV000624973	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-05-09	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130330	SCV001357798	likely benign	Hereditary cancer-predisposing syndrome	2018-11-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488657	SCV004241433	uncertain significance	not specified	2023-12-14	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.458-5delT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 249796 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.458-5delT has been reported in the literature in at least one individual affected with breast cancer (e.g., Tung_2014), however without strong evidence for causality (e.g., lack of co-segregation data). This report therefore does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication was ascertained in the context of this evaluation (PMID: 25186627). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as likely benign without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.