Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000200608 | SCV000255098 | uncertain significance | Familial cancer of breast | 2025-01-30 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1070 of the PALB2 protein (p.Leu1070Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 216752). 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 disruptive. Experimental studies have shown that this missense change affects PALB2 function (PMID: 31636395, 31757951, 33964450). 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 | RCV000568710 | SCV000665262 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-09-28 | criteria provided, single submitter | clinical testing | The p.L1070P variant (also known as c.3209T>C), located in coding exon 12 of the PALB2 gene, results from a T to C substitution at nucleotide position 3209. The leucine at codon 1070 is replaced by proline, an amino acid with similar properties. This alteration was identified in an individual diagnosed with breast cancer (Murali K et al. Hered Cancer Clin Pract, 2021 Aug;19:33). This alteration was found to be functionally abnormal in multiple homology-directed DNA repair (HDR) assays (Boonen RACM et al. Nat Commun, 2019 11;10:5296; Wiltshire T et al. Genet. Med., 2020 03;22:622-632; Brnich SE et al. J Mol Diagn, 2021 Jul;23:847-864). In addition, in a PARP inhibitor sensitivity assay, this alteration was found to be functionally inconclusive (Boonen RACM et al. Nat Commun, 2019 11;10:5296). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Fulgent Genetics, |
RCV002503787 | SCV002806974 | uncertain significance | Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3 | 2022-02-23 | criteria provided, single submitter | clinical testing | |
| CHEO Genetics Diagnostic Laboratory, |
RCV003150089 | SCV003838709 | uncertain significance | Breast and/or ovarian cancer | 2021-08-12 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV004719744 | SCV005325636 | uncertain significance | not provided | 2023-11-07 | criteria provided, single submitter | clinical testing | Observed in an individual with breast cancer and a family history of pancreatic cancer in published literature (PMID: 34399810); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31636395, 33169439, 32185139, 33195396, 32209438, 33964450, 19609323, 20871615, 24485656, 31757951, 34399810) |