ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1870G>A (p.Gly624Ser) (rs868760377)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219912 SCV000274550 likely benign Hereditary cancer-predisposing syndrome 2017-08-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Co-occurence with mutation in same gene (phase unknown),In silico models in agreement (benign)
Color RCV000219912 SCV000690230 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-03 criteria provided, single submitter clinical testing
Counsyl RCV000662524 SCV000785082 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-05-02 criteria provided, single submitter clinical testing
GeneDx RCV000657004 SCV000566081 uncertain significance not provided 2018-10-16 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1870G>A at the cDNA level, p.Gly624Ser (G624S) at the protein level, and results in the change of a Glycine to a Serine (GGC>AGC). This variant has been observed in at least one individual with breast cancer (Maxwell 2015). MSH6 Gly624Ser 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 Gly624Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000233003 SCV000283735 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-30 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 624 of the MSH6 protein (p.Gly624Ser). The glycine residue is moderately 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 an individual with breast cancer (PMID: 25503501). It has also been observed in an individual with clinical features of Lynch syndrome (Invitae); however, in this individual a pathogenic allele was also identified in MSH6, which suggests that this c.1870G>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 230869). General algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), and an algorithm developed specifically for the MSH6 gene (PMID: 23621914), suggest that this missense change is likely to be tolerated. However, these predictions have not been confirmed by published functional studies. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000484834 SCV000601521 uncertain significance not specified 2017-01-23 criteria provided, single submitter clinical testing

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