ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.642C>G (p.Tyr214Ter) (rs1800937)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075016 SCV000108236 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
GeneDx RCV000485263 SCV000567945 pathogenic not provided 2018-05-01 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.642C>G at the cDNA level and p.Tyr214Ter (Y214X) at the protein level. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAC>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in families with colorectal cancer and/or sebaceous adenomas (Verma 1999, Murphy 2008). Additionally, this variant has been observed in the compound heterozygous state with a second pathogenic MSH6 variant in a child with constitutional mismatch repair-deficiency (CMMR-D) syndrome (Scott 2007). Therefore, MSH6 Tyr214Ter is considered pathogenic.
Invitae RCV000703480 SCV000832383 pathogenic Hereditary nonpolyposis colorectal neoplasms 2018-05-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr214*) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with colorectal cancer (PMID: 10507723), as well as in an individual with metastatic prostate cancer (PMID: 27433846). Moreover, this variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with constitutional mismatch repair-deficiency (PMID: 17259933). ClinVar contains an entry for this variant (Variation ID: 89547). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001025256 SCV001187409 pathogenic Hereditary cancer-predisposing syndrome 2019-12-16 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)

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