Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000645858 | SCV000767613 | uncertain significance | Colorectal cancer, susceptibility to, 10 | 2017-11-04 | criteria provided, single submitter | clinical testing | In summary, this variant is a novel complex change with uncertain impact on protein function. 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. Experimental studies and prediction algorithms are not available for this complex variant, and the functional significance of replacing both amino acids is unknown. In addition, algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of both missense changes (p.Met1081Ile: SIFT: "Deleterious", PolyPhen-2: "Benign", Align-GVGD: "Class C0"; and p.Arg1082Val: SIFT: "Deleterious", PolyPhen-2: "Probably Damaging", Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with POLD1-related disease. This variant is not present in population databases (ExAC no frequency). This complex sequence change replaces methionine with isoleucine at codon 1081 and arginine with valine at codon 1082 of the POLD1 protein (p.Met1081_Arg1082delinsIleVal). The methionine residue at codon 1081 is highly conserved and there is a small physicochemical difference between methionine and isoleucine. The arginine residue at codon 1082 is highly conserved and there is a moderate physicochemical difference between arginine and valine. |