ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.267C>G (p.Asp89Glu) (rs762818044)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204000 SCV000260706 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-06 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 89 of the MSH6 protein (p.Asp89Glu). The aspartic acid residue is weakly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is present in population databases (rs762818044, ExAC 0.003%) but has not been reported in the literature in individuals with a MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 220279). 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"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on mRNA splicing and 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 RCV000587576 SCV000279379 uncertain significance not provided 2017-12-11 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.267C>G at the cDNA level, p.Asp89Glu (D89E) at the protein level, and results in the change of an Aspartic Acid to a Glutamic Acid (GAC>GAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Asp89Glu was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Aspartic Acid and Glutamic Acid share similar properties, this is considered a conservative amino acid substitution. MSH6 Asp89Glu is not located in a known functional domain. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether MSH6 Asp89Glu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000491184 SCV000580188 uncertain significance Hereditary cancer-predisposing syndrome 2016-11-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Integrated Genetics/Laboratory Corporation of America RCV000587576 SCV000695824 uncertain significance not provided 2016-05-09 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.267C>G (p.Asp89Glu) variant involves the alteration of a non-conserved nucleotide with 3/3 in silico tools ((SNPs&GO and MutationTaster not captured due to low reliability index and p-value, respectively) predicting a benign outcome, although these predictions have yet to be functionally assessed. This variant was observed in the large, broad control population, ExAC, with an allele frequency of 2/121386 (1/60693, allele frequency 0.0000165), which does not exceed the estimated maximal expected allele frequency for a pathogenic MSH6 variant of 1/7037 (allele frequency: 0.0001421). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories. Because of the absence of clinical information and the lack of functional studies, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Counsyl RCV000662780 SCV000785589 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-09-26 criteria provided, single submitter clinical testing
Color RCV000491184 SCV000904013 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-11 criteria provided, single submitter clinical testing

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