Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000114623 | SCV000219077 | likely benign | Familial cancer of breast | 2024-01-17 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000481742 | SCV000565356 | uncertain significance | not provided | 2023-07-31 | criteria provided, single submitter | clinical testing | 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; Published functional studies demonstrate intact or reduced homology-directed repair, normal or increased PARP inhibitor sensitivity, decreased BRCA2 binding, moderate cytoplasmic accumulation, and larger RAD51 foci formation (Boonen et al., 2019; Rodrigue et al., 2019; Wiltshire et al., 2020); Observed in individuals with a personal and family history of breast cancer (Catucci et al., 2012; Nguyen-Dumont et al., 2015); This variant is associated with the following publications: (PMID: 25575445, 22692731, 31586400, 31636395, 33195396, 31757951, 24485656, 19609323, 20871615, 33809179) |
Ambry Genetics | RCV000574823 | SCV000665409 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-12-06 | criteria provided, single submitter | clinical testing | The p.L1119P variant (also known as c.3356T>C), located in coding exon 13 of the PALB2 gene, results from a T to C substitution at nucleotide position 3356. The leucine at codon 1119 is replaced by proline, an amino acid with similar properties. In a study assessing the contribution of PALB2 mutations to high-risk Jewish breast and ovarian cancer families, this alteration was detected in one Moroccan proband (1/97 cases) and in 0/109 ethnically-matched controls (Catucci I et al. Fam. Cancer. 2012 Sep;11:483-91). This variant was also detected in 1/1240 BRCA1/2-negative individuals recruited from the Breast Cancer Family Registry (Nguyen-Dumont T et al. Breast Cancer Res. Treat. 2015 Jan;149:547-54). In a homology-directed DNA repair (HDR) assay, this alteration was found to be functionally normal (Wiltshire T et al. Genet. Med., 2019 Oct, Boonen et al. Nat. Comms. 2019 Nov). In a PARP inhibitor sensitivity assay, this alteration was found to be functionally normal (Boonen et al. Nat. Comms. 2019 Nov, Rodrigue et al. NAR. 2019 Nov). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Color Diagnostics, |
RCV000574823 | SCV000686033 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-11-22 | criteria provided, single submitter | clinical testing | This missense variant replaces leucine with proline at codon 1119 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown the mutant protein to exhibit normal expression and wild type-like homologous recombination activity (PMID: 31757951, 31636395). This variant has been reported in individuals affected with breast cancer (PMID: 22692731, 25575445), as well as in unaffected individuals (Color internal data). This variant has been identified in 4/251288 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
Counsyl | RCV000114623 | SCV000785030 | uncertain significance | Familial cancer of breast | 2017-03-17 | criteria provided, single submitter | clinical testing | |
Myriad Genetics, |
RCV000114623 | SCV004019672 | uncertain significance | Familial cancer of breast | 2023-03-31 | criteria provided, single submitter | clinical testing | This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. |
Leiden Open Variation Database | RCV000114623 | SCV001193401 | uncertain significance | Familial cancer of breast | 2019-05-13 | no assertion criteria provided | curation | Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. |