ClinVar Miner

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

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Total submissions: 7
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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 2018-08-16 criteria provided, single submitter clinical testing In silico models in agreement (benign)
Invitae RCV000233003 SCV000283735 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-05 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.
GeneDx RCV000657004 SCV000566081 uncertain significance not provided 2020-11-09 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer (Maxwell 2015); This variant is associated with the following publications: (PMID: 21097718, 23621914, 25503501, 30212499, 31762146)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000484834 SCV000601521 uncertain significance not specified 2017-01-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000219912 SCV000690230 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-31 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000484834 SCV001338333 uncertain significance not specified 2020-02-25 criteria provided, single submitter clinical testing Variant summary: MSH6 c.1870G>A (p.Gly624Ser) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250392 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1870G>A has been reported in the literature in individuals affected with breast cancer (Maxwell_2014, Bradbury_2018). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, five classified as VUS while one classified as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.

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