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

Total submissions: 7

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.