Submissions for variant NM_000179.2(MSH6):c.2417C>G (p.Ser806Cys) (rs372990379)

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Total submissions: 6

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160717	SCV000211351	uncertain significance	not provided	2017-07-03	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.2417C>G at the cDNA level, p.Ser806Cys (S806C) at the protein level, and results in the change of a Serine to a Cysteine (TCC>TGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ser806Cys was observed at an allele frequency of 0.05% (5/10286) in individuals of African ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Serine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Ser806Cys occurs at a position that is not conserved and is located in the Lever domain (Warren 2007, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MSH6 Ser806Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl	RCV000409643	SCV000488052	uncertain significance	Hereditary nonpolyposis colorectal cancer type 5	2015-12-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000570608	SCV000669888	uncertain significance	Hereditary cancer-predisposing syndrome	2018-02-16	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae	RCV000629702	SCV000750658	uncertain significance	Hereditary nonpolyposis colon cancer	2018-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces serine with cysteine at codon 806 of the MSH6 protein (p.Ser806Cys). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is present in population databases (rs372990379, ExAC 0.05%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 182661). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160717	SCV000888256	uncertain significance	not provided	2018-07-10	criteria provided, single submitter	clinical testing
Color	RCV000570608	SCV000903876	uncertain significance	Hereditary cancer-predisposing syndrome	2018-06-03	criteria provided, single submitter	clinical testing

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