ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2653A>T (p.Lys885Ter) (rs587782593)

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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 RCV000131937 SCV000186993 pathogenic Hereditary cancer-predisposing syndrome 2016-11-30 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000578967 SCV000680903 pathogenic not provided 2018-01-26 criteria provided, single submitter clinical testing The K885X variant in the MSH6 gene has been reported previously in an individual with breast cancer (Tedaldi et al, 2017). The International Society for Gastroinestinal Hereditary Tumors Incorporated (InSiGHT) classifies this variant as pathogenic (Thompson et al., 2014). The K885X variant is not observed in large population cohorts (Lek et al., 2016). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Loss-of-function variants are known to be pathogenic in this gene associated with Lynch syndrome. Based on the ACMG recommendations, K885X is interpreted as a known pathogenic sequence change.
Invitae RCV001046832 SCV001210750 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-02-01 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys885*) 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 observed as homozygous in an individual affected with constitutional mismatch repair deficiency syndrome (PMID: 30013564) and as heterozygous in an individual affected with breast cancer (PMID: 28423363). It has also been reported in an individual who was referred for hereditary cancer genetic testing (PMID: 28514183). ClinVar contains an entry for this variant (Variation ID: 142620). 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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