ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1599G>C (p.Glu533Asp) (rs373726731)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000524115 SCV000166212 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 533 of the MSH6 protein (p.Glu533Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is present in population databases (rs373726731, ExAC 0.01%). This variant has been reported in individuals affected with breast cancer (PMID: 26845104, 26976419). ClinVar contains an entry for this variant (Variation ID: 135830). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD)  and an algorithm developed to predict the effect of missense changes in MSH6 (PMID: 23621914) all suggest that this variant is likely to be tolerated, but 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.
University of Washington Department of Laboratory Medicine,University of Washington RCV000122952 SCV000266202 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV000219239 SCV000276977 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000218729 SCV000279307 uncertain significance not provided 2018-05-31 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1599G>C at the cDNA level, p.Glu533Asp (E533D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAG>GAC). This variant has been reported in at least two individuals with breast cancer and another with breast and/or ovarian cancer (Shirts 2016, Tung 2016, Maxwell 2016). MSH6 Glu533Asp 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 information, it is unclear whether MSH6 Glu533Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl RCV000411179 SCV000489645 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-11-01 criteria provided, single submitter clinical testing
Color RCV000219239 SCV000685206 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780476 SCV000917757 uncertain significance not specified 2018-04-13 criteria provided, single submitter clinical testing Variant summary: MSH6 c.1599G>C (p.Glu533Asp) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. However, these predictions have yet to be functionally assessed. The variant was observed with an allele frequency of 2e-05 in 246116 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MSH6 causing Lynch Syndrome (2e-05 vs 0.00014), allowing no conclusion about variant significance. The variant, c.1599G>C, has been reported in the literature in individuals affected with Lynch Syndrome and Breast Cancer (Lu_2015, Shirts_2015, Tung_2016). These report(s) 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. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as uncertain significance.

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