ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1739C>T (p.Ser580Leu) (rs41295270)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131189 SCV000186139 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000524119 SCV000254280 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-01 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 580 of the MSH6 protein (p.Ser580Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs41295270, ExAC 0.01%). This variant has been reported in the literature in individuals affected with Lynch syndrome and colorectal cancer (PMID: 18269114, 18033691). ClinVar contains an entry for this variant (Variation ID: 89219). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be deleterious (PMID: 23621914). However, this prediction has not been confirmed by published functional studies and its clinical significance is uncertain. 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 RCV000131189 SCV000537562 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-14 criteria provided, single submitter clinical testing
GeneDx RCV000485534 SCV000565217 uncertain significance not provided 2018-01-10 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1739C>T at the cDNA level, p.Ser580Leu (S580L) at the protein level, and results in the change of a Serine to a Leucine (TCG>TTG). This variant has been observed in at least one proband with a Lynch-syndrome associated cancer, as well as in another individual with colorectal cancer whose tumor testing demonstrated microsatellite stability (MSS) and retention of all four mismatch repair proteins via immunohistochemistry (Barnetson 2008, Devlin 2008). In addition, the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as being of uncertain significance based on insufficient evidence (Thompson 2014). MSH6 Ser580Leu was observed at an allele frequency of 0.01% (3/30,782) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is located in the Connector domain (Warren 2007, Kansikas 2011). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Ser580Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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