ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1786T>A (p.Phe596Ile) (rs587779918)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115383 SCV000149292 uncertain significance not provided 2017-07-17 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1786T>A at the cDNA level, p.Phe596Ile (F596I) at the protein level, and results in the change of a Phenylalanine to an Isoleucine (TTT>ATT). This variant was observed in an individual with ovarian cancer and in another with colorectal or endometrial cancer (Baglietto 2010, Pal 2012). MSH6 Phe596Ile was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Phenylalanine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. MSH6 Phe596Ile occurs at a position that is conserved across species and is located within the Connector domain (Warren 2007, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Phe596Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000233835 SCV000283727 uncertain significance Hereditary nonpolyposis colon cancer 2019-11-24 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with isoleucine at codon 596 of the MSH6 protein (p.Phe596Ile). The phenylalanine residue is moderately conserved and there is a small physicochemical difference between phenylalanine and isoleucine. This variant is present in population databases (rs587779918, ExAC 0.001%). This variant has been reported in an individual affected with colorectal or endometrial cancer (PMID: 20028993) and in an individual with ovarian cancer (PMID: 23047549). ClinVar contains an entry for this variant (Variation ID: 127564). 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this is a rare missense change with uncertain impact on protein function. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000409692 SCV000489120 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-08-22 criteria provided, single submitter clinical testing
Ambry Genetics RCV000562745 SCV000669912 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-15 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000562745 SCV000911937 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-11 criteria provided, single submitter clinical testing

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