ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2579C>T (p.Ser860Phe) (rs370412074)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164156 SCV000214772 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000478111 SCV000568043 uncertain significance not provided 2015-09-28 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2579C>T at the cDNA level, p.Ser860Phe (S860F) at the protein level, and results in the change of a Serine to a Phenylalanine (TCT>TTT). This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. MSH6 Ser860Phe was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Serine and Phenylalanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Ser860Phe occurs at a position that is conserved across species and is located in the MutS domain (Terui 2013). 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 Ser860Phe is pathogenic or benign.
Invitae RCV000693101 SCV000820956 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-15 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 860 of the MSH6 protein (p.Ser860Phe). The serine residue is highly conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is present in population databases (rs370412074, ExAC 0.002%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 184831). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be deleterious (PMID: 23621914). However, this prediction has not been confirmed by published functional studies and its clinical significance is uncertain. 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.

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