ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1858G>A (p.Gly620Ser) (rs876661043)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000215890 SCV000279329 uncertain significance not provided 2018-12-05 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1858G>A at the cDNA level, p.Gly620Ser (G620S) at the protein level, and results in the change of a Glycine to a Serine (GGT>AGT). This variant has been observed in an individual with pancreatic cancer and in an individual undergoing multi-gene panel testing due to a Lynch syndrome-associated cancer and/or polyps (Yurgelun 2015, Chaffee 2018). MSH6 Gly620Ser was not observed at a significant allele frequency 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 that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Gly620Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000225881 SCV000283733 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-18 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 620 of the MSH6 protein (p.Gly620Ser). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with pancreatic cancer, and suspected Lynch syndrome (PMID: 28726808, 25980754). ClinVar contains an entry for this variant (Variation ID: 234483). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their 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.
Ambry Genetics RCV000569553 SCV000662369 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-20 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Counsyl RCV000662360 SCV000784745 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2018-02-15 criteria provided, single submitter clinical testing
Color RCV000569553 SCV000911026 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-02 criteria provided, single submitter clinical testing

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