ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.431A>G (p.His144Arg) (rs755709875)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000476907 SCV000544002 uncertain significance Colorectal cancer, susceptibility to, 12 2020-01-08 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 144 of the POLE protein (p.His144Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs755709875, ExAC 0.02%). This variant has been observed in an individual affected with colorectal cancer (PMID: 29212164). ClinVar contains an entry for this variant (Variation ID: 405687). 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"). 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 RCV000563876 SCV000671272 uncertain significance Hereditary cancer-predisposing syndrome 2015-07-01 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Fulgent Genetics,Fulgent Genetics RCV000763819 SCV000894736 uncertain significance Colorectal cancer, susceptibility to, 12; Facial dysmorphism, immunodeficiency, livedo, and short stature 2018-10-31 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000826023 SCV000967512 uncertain significance not specified 2018-08-14 criteria provided, single submitter clinical testing The p.His144Arg variant in POLE has not been previously reported in individuals with colorectal cancer but has been reported by other clinical laboratories in C linVar (Variation ID: 405687). It has also been identified in 3/30758 South Asia n chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadins; dbSNP rs755709875). Computational prediction tools and conservation analysis suggest that the p.His144Arg variant may impact the protein, though thi s information is not predictive enough to determine pathogenicity. In summary, t he clinical significance of the p.His144Arg variant is uncertain. ACMG/AMP Crite ria applied: PP3, PM2.

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