Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000214682 | SCV000274185 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-03-14 | criteria provided, single submitter | clinical testing | The p.L24S variant (also known as c.71T>C), located in coding exon 2 of the PALB2 gene, results from a T to C substitution at nucleotide position 71. The leucine at codon 24 is replaced by serine, an amino acid with dissimilar properties. This alteration has been reported in at least one breast cancer patient in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). This alteration was found to be functionally abnormal in a homology-directed DNA repair (HDR) assay (Wiltshire T et al. Genet Med, 2020 03;22:622-632). 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. |
| Invitae | RCV000474579 | SCV000550649 | uncertain significance | Familial cancer of breast | 2023-07-17 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 24 of the PALB2 protein (p.Leu24Ser). 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: 230588). 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. |
| Color Diagnostics, |
RCV000214682 | SCV000914005 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-08-15 | criteria provided, single submitter | clinical testing | This missense variant replaces leucine with serine at codon 24 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). Functional studies have reported that this variant disrupts PALB2 function in homology-directed DNA repair, BRCA1 and BRCA2 association, sensitivity to PARP inhibitors and DNA damage response (PMID: 31636395, 31757951, 33964450). This variant has been detected in a breast cancer case-control meta-analysis in 0/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010715). This variant has not been identified 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. |