Submissions for variant NM_000179.2(MSH6):c.3529C>G (p.Leu1177Val) (rs748398941)

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Total submissions: 5

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000469909	SCV000551098	uncertain significance	Hereditary nonpolyposis colon cancer	2019-10-22	criteria provided, single submitter	clinical testing	This sequence change replaces leucine with valine at codon 1177 of the MSH6 protein (p.Leu1177Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs748398941, ExAC 0.02%) but has not been reported in the literature in individuals with a MSH6-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000521217	SCV000618484	uncertain significance	not provided	2017-05-25	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3529C>G at the cDNA level, p.Leu1177Val (L1177V) at the protein level, and results in the change of a Leucine to a Valine (CTT>GTT). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in a breast tumor (Gellert 2016). MSH6 Leu1177Val was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Leucine and Valine share similar properties, this is considered a conservative amino acid substitution. MSH6 Leu1177Val occurs at a position that is conserved across species and is located in the ATPase domain (Warren 2007, Kansikas 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Leu1177Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000568727	SCV000669922	uncertain significance	Hereditary cancer-predisposing syndrome	2018-10-03	criteria provided, single submitter	clinical testing	Insufficient evidence
Counsyl	RCV000663017	SCV000786035	uncertain significance	Hereditary nonpolyposis colorectal cancer type 5	2018-02-09	criteria provided, single submitter	clinical testing
Color	RCV000568727	SCV001341544	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-21	criteria provided, single submitter	clinical testing

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