ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.4004A>C (p.Glu1335Ala) (rs564434147)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129804 SCV000184615 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000204360 SCV000261608 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-12 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 1335 of the MSH6 protein (p.Glu1335Ala). The glutamic acid residue is weakly conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is present in population databases (rs564434147, ExAC 0.04%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with Lynch syndrome and astrocytoma (PMID: 23523604, 24073290). ClinVar contains an entry for this variant (Variation ID: 141327). 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: "Probably 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000656905 SCV000339599 uncertain significance not provided 2016-02-04 criteria provided, single submitter clinical testing
Counsyl RCV000409369 SCV000489131 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-08-25 criteria provided, single submitter clinical testing
GeneDx RCV000656905 SCV000565241 uncertain significance not provided 2018-01-24 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.4004A>C at the cDNA level, p.Glu1335Ala (E1335A) at the protein level, and results in the change of a Glutamic Acid to an Alanine (GAA>GCA). This variant has been reported in an individual with a personal history of breast and/or ovarian cancer, as well as an individual with an astrocytoma (Rodriguez-Hernandez 2013, Cock-Rada 2017). Additionally, this variant was observed in a proband with colorectal cancer, whose tumor testing demonstrated microsatellite stability (MSS) and retention of all four mismatch repair proteins via immunohistochemistry (Perez-Cabornero 2013). MSH6 Glu1335Ala was observed at an allele frequency of 0.03% (9/28,764) in individuals of South Asian ancestry in large population cohorts (Lek 2016). MSH6 Glu1335Ala is located in the MSH2 binding site and ATPase domain (Kariola 2002, 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 Glu1335Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000129804 SCV000685482 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-13 criteria provided, single submitter clinical testing
Mendelics RCV000708898 SCV000837935 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing

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