ClinVar Miner

Submissions for variant NM_001256849.1(POLD1):c.1157G>A (p.Arg386His) (rs764023083)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000563945 SCV000670957 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Fulgent Genetics,Fulgent Genetics RCV000764217 SCV000895220 uncertain significance Colorectal cancer 10; Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000233864 SCV000287505 uncertain significance Colorectal cancer 10 2019-01-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 386 of the POLD1 protein (p.Arg386His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs764023083, ExAC 0.006%). This variant has not been reported in the literature in individuals with POLD1-related disease. ClinVar contains an entry for this variant (Variation ID: 239224). 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: "Benign"; 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000602237 SCV000712905 uncertain significance not specified 2017-03-09 criteria provided, single submitter clinical testing The p.Arg386His variant in POLD1 has not been previously reported in individuals with colorectal cancer, but has been reported by other clinical laboratories in ClinVar (Variation ID 239224). It has been identified in 2/30782 South Asian ch romosomes and 1/9850 Ashkenazi Jewish chromosomes by the Genome Aggregation Data base (gnomAD,; dbSNP rs764023083). Computationa l prediction tools and conservation analysis suggest that the p.Arg386His varian t may not impact the protein, though this information is not predictive enough t o rule out pathogenicity. In summary, the clinical significance of the p.Arg386H is variant is uncertain. ACMG/AMP Criteria applied: PM2, BP4.

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