Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000645888 | SCV000767643 | uncertain significance | Colorectal cancer, susceptibility to, 10 | 2024-01-25 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 197 of the POLD1 protein (p.Ser197Arg). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with colon polyps and breast cancer (PMID: 30374176). ClinVar contains an entry for this variant (Variation ID: 537130). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. |
| University of Washington Department of Laboratory Medicine, |
RCV000757928 | SCV000886448 | likely benign | Familial colorectal cancer | 2018-05-09 | criteria provided, single submitter | research | The POLD1 variant designated as NM_002878.3:c.394G>A (p.Val132Ile) is classified as likely benign. In one observed family, a family with the variant had colon polyps that did not show the molecular ultramutation phenotype that is the signature of pathogenic POLD1 mutations (Briggs et al, 2013, PMID: 23447401). This variant is not in the POLD1 exonuclease domain and is unlikely to cause increased cancer risk, as only POLD1 variants that alter exonuclease activity have been documented to be associated with colon and endometrial cancer risk. Additionally, in the same family, in the POLD1 variant often co-occurs with a likely-pathogenic mutation in the CHEK2 gene (p.R145W). Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives about 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter POLD1 function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. |