ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.218A>G (p.Asp73Gly) (rs1060500786)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000460560 SCV000543937 uncertain significance Colorectal cancer, susceptibility to, 12 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 73 of the POLE protein (p.Asp73Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with POLE-related disease. ClinVar contains an entry for this variant (Variation ID: 405626). 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: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000826024 SCV000967513 uncertain significance not specified 2018-08-14 criteria provided, single submitter clinical testing The p.Asp73Gly variant in POLE has not been previously reported in individuals w ith colorectal cancer but has been reported by other clinical laboratories in Cl inVar (Variation ID: 405626). It has also been identified in 1/111706 European c hromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstit Computational prediction tools and conservation analysis suggest that the p.Asp73Gly variant may impact the protein, though this information is not pr edictive enough to determine pathogenicity. In summary, the clinical significanc e of the p.Asp73Gly variant is uncertain. ACMG/AMP Criteria applied: PP3, PM2.

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