Submissions for variant NM_000179.2(MSH6):c.979A>G (p.Thr327Ala) (rs730881814)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160712	SCV000211343	uncertain significance	not provided	2018-11-26	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.979A>G at the cDNA level, p.Thr327Ala (T327A) at the protein level, and results in the change of a Threonine to an Alanine (ACT>GCT). This variant has been reported in an individual with melanoma (Yehia 2018). MSH6 Thr327Ala was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the nuclear localization signal (Gassman 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 Thr327Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000214500	SCV000272957	uncertain significance	Hereditary cancer-predisposing syndrome	2017-11-03	criteria provided, single submitter	clinical testing	Insufficient or conflicting evidence
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000499861	SCV000592579	uncertain significance	Lynch syndrome	2014-01-17	criteria provided, single submitter	clinical testing
Invitae	RCV000818095	SCV000958690	uncertain significance	Hereditary nonpolyposis colon cancer	2019-11-25	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with alanine at codon 327 of the MSH6 protein (p.Thr327Ala). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs730881814, ExAC 0.003%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 182657). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their 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.