Submissions for variant NM_000179.3(MSH6):c.2260dup (p.Thr754fs)

dbSNP: rs1553413640

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000629769	SCV000750725	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-01-27	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 525640). For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr754Asnfs*2) 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).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759852	SCV000889473	pathogenic	not provided	2018-01-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193096	SCV001361703	likely pathogenic	Hereditary nonpolyposis colon cancer	2019-01-25	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.2260dupA (p.Thr754AsnfsX2) 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 (e.g. c.2503C>T (p.Gln835X), c.2731C>T (p.Arg911X), and c.2764C>T (p.Arg922X)). The variant was absent in 245798 control chromosomes (gnomAD). To our knowledge, no occurrence of c.2260dupA in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Myriad Genetics, Inc.	RCV003451485	SCV004187251	pathogenic	Lynch syndrome 5	2023-08-16	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.