Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001326173 | SCV001517187 | uncertain significance | Familial cancer of breast | 2023-05-04 | criteria provided, single submitter | clinical testing | 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PALB2 protein function. ClinVar contains an entry for this variant (Variation ID: 1025812). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. This variant is present in population databases (rs753012991, gnomAD 0.004%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 622 of the PALB2 protein (p.Leu622Pro). |
| Color Diagnostics, |
RCV001525969 | SCV001736196 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-05-17 | criteria provided, single submitter | clinical testing | This missense variant replaces leucine with proline at codon 622 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 that the variant protein retained ~80% of normal PALB2 protein activity to rescue the DNA repair and checkpoint defects in PALB2 knockout mouse embryonic stem cells (PMID: 31757951). This variant has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010704). This variant has been identified in 5/251296 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. |
| Ambry Genetics | RCV001525969 | SCV002724133 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-04-17 | criteria provided, single submitter | clinical testing | The p.L622P variant (also known as c.1865T>C), located in coding exon 5 of the PALB2 gene, results from a T to C substitution at nucleotide position 1865. The leucine at codon 622 is replaced by proline, an amino acid with similar properties. In one functional study, this variant did not significantly impair homologous recombination efficiency compared to wild-type, and was classified as a variant of uncertain significance by the authors (Boonen RACM et al. Nat Commun, 2019 11;10:5296). 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. |
| Baylor Genetics | RCV001326173 | SCV004202047 | uncertain significance | Familial cancer of breast | 2023-10-10 | criteria provided, single submitter | clinical testing |