Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000133512 | SCV000488503 | likely pathogenic | Colorectal cancer, susceptibility to, 10 | 2016-06-10 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV000568467 | SCV000676200 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-02-27 | criteria provided, single submitter | clinical testing | The p.L474P pathogenic mutation (also known as c.1421T>C), located in coding exon 11 of the POLD1 gene, results from a T to C substitution at nucleotide position 1421. The leucine at codon 474 is replaced by proline, an amino acid with similar properties. This variant is located within the highly conserved exonuclease domain of the POLD1 gene. This alteration was first reported in a female patient diagnosed with a colon cancer and a synchronous gastrointestinal stromal tumor (GIST) in the large bowel at age 36, whose family also met Amsterdam II criteria. Authors described this alteration as pathogenic, supported by cosegregation in the family, in silico predictions, previously published yeast assays, as well as the fact that this alteration's location is paralogous to the well described residue in POLE where the recurrent p.L424V mutation occurs (Valle L et al. Hum. Mol. Genet. 2014 Jul; 23(13):3506-12). The yeast based functional assay that the authors of Valle et al. describe was performed on the homologous residue (p.L479 Pol3) in yeast, and was shown to cause a mutator phenotype (Murphy K et al. Genome 2006 Apr; 49(4):403-10). This alteration has also been described in a woman with colorectal cancer and gastric polyps at age 23 as well as benign esophageal tumor at age 25. This alteration was also shown to segregate with disease in the family (Bellido F et al, Genet. Med. 2015 Jul;2). In addition, this alteration was identified in two Spanish families with colorectal cancer and breast cancer and is suggested to be a Spanish founder mutation. The tumor of one proband, which exhibited MSI and loss of MLH1 and PMS2 on IHC, had two MLH1 mutations. The authors posited that these somatic MLH1 mutations were a consequence of POLD1 inactivation (Ferrer-Avargues R et al. J Gene Med. 2017 Apr;19(4)). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Invitae | RCV000133512 | SCV001579554 | pathogenic | Colorectal cancer, susceptibility to, 10 | 2022-08-21 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 144003). This missense change has been observed in individual(s) with colorectal cancer, endometrial cancer, breast cancer and gastrointestinal stromal tumor (PMID: 24501277, 26133394, 28306219). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 474 of the POLD1 protein (p.Leu474Pro). |
| Myriad Genetics, |
RCV000133512 | SCV004018533 | likely pathogenic | Colorectal cancer, susceptibility to, 10 | 2023-04-19 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 24501277, 26133394, 28306219]. This variant is expected to disrupt protein structure [Myriad internal data]. |
| Baylor Genetics | RCV000133512 | SCV004203506 | pathogenic | Colorectal cancer, susceptibility to, 10 | 2021-11-08 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000133512 | SCV000188587 | risk factor | Colorectal cancer, susceptibility to, 10 | 2014-07-01 | no assertion criteria provided | literature only |