ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.742del (p.Arg248fs) (rs587781691)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129856 SCV000184673 pathogenic Hereditary cancer-predisposing syndrome 2016-12-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000657423 SCV000779158 pathogenic not provided 2017-11-29 criteria provided, single submitter clinical testing This deletion of one nucleotide in MSH6 is denoted c.742delC at the cDNA level and p.Arg248GlufsX31 (R248EfsX31) at the protein level. The normal sequence, with the base that is deleted in brackets, is TAAAAAAA[delC]GAAG. The deletion causes a frameshift which changes an Arginine to a Glutamic Acid at codon 248, and creates a premature stop codon at position 31 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH6 c.742delC has been his variant has been reported in a validation study of pathogenic hereditary cancer variants identified on whole exome sequencing (LaDuca 2017). We consider this variant to be pathogenic.
Invitae RCV000477160 SCV000551199 pathogenic Hereditary nonpolyposis colon cancer 2018-11-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg248Glufs*31) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs587781691, ExAC 0.002%). This variant has been observed in individuals undergoing Lynch syndrome testing (PMID: 28514183). ClinVar contains an entry for this variant (Variation ID: 141365). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.

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