ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.854G>T (p.Ser285Ile) (rs63750878)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212635 SCV000211264 uncertain significance not provided 2017-12-07 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.854G>T at the cDNA level, p.Ser285Ile (S285I) at the protein level, and results in the change of a Serine to an Isoleucine (AGT>ATT). This variant was observed in an individual with a personal history of a MSI-L colon cancer and a family history of colon, breast and ovarian cancer (Kolodner 1999). Functional assays have had disparate results, showing that MSH6 Ser285Ile does not affect nuclear transport of MSH6 nor ATP hydrolysis and is not resistant to DNA damaging agents, but does exhibit a decreased ability to bind ATP and alters subcellular localization (Cyr 2008, Gassman 2011, Belvederesi 2012, Houlleberghs 2017). MSH6 Ser285Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Serine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Ser285Ile is located in the nuclear localization signals (Gassman 2011). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Ser285Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000160657 SCV000214780 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Intact protein function observed in appropriate functional assay(s)
Invitae RCV000556949 SCV000625012 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-13 criteria provided, single submitter clinical testing This sequence change replaces serine with isoleucine at codon 285 of the MSH6 protein (p.Ser285Ile). The serine residue is weakly conserved and there is a large physicochemical difference between serine and isoleucine. This variant is present in population databases (rs63750878, ExAC 0.002%). This variant has been reported in an individual affected with colorectal cancer (PMID: 10537275), and a family affected with Lynch syndrome (PMID: 18790734). ClinVar contains an entry for this variant (Variation ID: 89571). Experimental studies demonstrate that this missense change results in normal MSH2 binding, modestly reduced ATPase activity, and does not appear to affect DNA mismatch repair (MMR) activity (PMID: 18790734, 28531214). This variant may affect nuclear localization of MSH6, but results from in vitro studies are conflicting (PMID: 22851212, 21437237). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000160657 SCV000690483 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-20 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148648 SCV000190363 uncertain significance Colorectal cancer 2014-06-01 no assertion criteria provided research

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