ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3312T>A (p.Phe1104Leu) (rs747441460)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205915 SCV000262316 uncertain significance Hereditary nonpolyposis colon cancer 2018-05-02 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 1104 of the MSH6 protein (p.Phe1104Leu). The phenylalanine residue is moderately conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs747441460, ExAC 0.03%). This variant has not been reported in the literature in individuals with an MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 221123). 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.
Ambry Genetics RCV000216977 SCV000277901 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000486074 SCV000567484 uncertain significance not provided 2015-07-30 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3312T>A at the cDNA level, p.Phe1104Leu (F1104L) at the protein level, and results in the change of a Phenylalanine to a Leucine (TTT>TTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Phe1104Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Phenylalanine and Leucine share similar properties, this is considered a conservative amino acid substitution. MSH6 Phe1104Leu occurs at a position that is conserved across species and is located in domain V of the MutS domain (Terui 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH6 Phe1104Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Fulgent Genetics,Fulgent Genetics RCV000764432 SCV000895489 uncertain significance Endometrial carcinoma; Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 5 2018-10-31 criteria provided, single submitter clinical testing

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