Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002281805 | SCV002572244 | likely pathogenic | Malignant tumor of breast | 2022-08-22 | criteria provided, single submitter | clinical testing | Variant summary: The variant identified by MLPA or other technology involves the deletion of exon 13 (i.e. the last exon) in the PALB2 gene. A presumed nomenclature of c.(3350+1_3351-1)_(*298_?)del has been designated for the purposes of this classification. Although exact breakpoints of this deletion are not known, it is not expected to cause nonsense mediated decay (NMD), but is predicted to cause a large truncation of the encoded protein (removing amino acids 1117-1186, and likely replacing it with an incorrect sequence). This variant affects the WD40 domain (IPR031920; amino acids 840-1184), which is required to bind to the N-terminus of BRCA2, and localization of BRCA2 to nuclear foci requires its association with PALB2 (PMID: 19609323). Several truncating variants are reported within the last exon in affected individuals (HGMD). The variant was absent in 21694 control chromosomes (gnomAD database, structural variants dataset). Deletions of exon 13 in the PALB2 gene have been reported in the literature in individuals affected with breast- and ovarian cancer (Antoniou_2014, Norquist_2016, Lilyquist_2017). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |