Submissions for variant NM_000179.2(MSH6):c.3824G>A (p.Cys1275Tyr) (rs150990541)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656904	SCV000149333	uncertain significance	not provided	2018-04-26	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3824G>A at the cDNA level, p.Cys1275Tyr (C1275Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGT>TAT). This variant was observed in at least one individual with breast cancer (Tung 2015). MSH6 Cys1275Tyr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the ATPase 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 Cys1275Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000119134	SCV000153848	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2019-11-29	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine with tyrosine at codon 1275 of the MSH6 protein (p.Cys1275Tyr). The cysteine residue is weakly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is present in population databases (rs150990541, ExAC 0.003%). This variant has been reported in the literature in an individual affected with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 127594). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be deleterious (PMID: 23621914). However, this prediction has not been confirmed by published functional studies and its 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	RCV000115424	SCV000185242	uncertain significance	Hereditary cancer-predisposing syndrome	2018-12-07	criteria provided, single submitter	clinical testing	Insufficient or Conflicting Evidence
Counsyl	RCV000410495	SCV000487844	uncertain significance	Hereditary nonpolyposis colorectal cancer type 5	2015-12-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656904	SCV000601588	uncertain significance	not provided	2018-12-03	criteria provided, single submitter	clinical testing
Color	RCV000115424	SCV000685447	uncertain significance	Hereditary cancer-predisposing syndrome	2019-11-05	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV001194392	SCV001363900	uncertain significance	not specified	2019-10-03	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3824G>A (p.Cys1275Tyr) results in a non-conservative amino acid change located in the ATPase domain of DNA mismatch repair MUTS family 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 2.4e-05 in 250998 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3824G>A has been reported in the literature in individuals affected with cancer (Lu_2015, Tung_2014). 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 ClinVar submissions (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.