Submissions for variant NM_000179.3(MSH6):c.517_520del (p.Leu173fs)

dbSNP: rs1553411419

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000546537	SCV000624976	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2017-02-18	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, loss-of-function variants in MSH6 are known to be pathogenic (PMID: 24362816, 18269114). This sequence change deletes 4 nucleotides from exon 3 of the MSH6 mRNA (c.517_520delCTGA), causing a frameshift at codon 173. This creates a premature translational stop signal (p.Leu173Glufs*10) and is expected to result in an absent or disrupted protein product.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193726	SCV001362784	likely pathogenic	Hereditary nonpolyposis colon cancer	2019-07-11	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.517_520delCTGA (p.Leu173GlufsX10) 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 251438 control chromosomes (gnomAD). To our knowledge, no occurrence of c.517_520delCTGA in individuals affected with Hereditary Non-Polyposis Colon Cancer and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.