ClinVar

Description

Variant summary: PALB2 c.1317delG (p.Phe440LeufsX12) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 249846 control chromosomes. c.1317delG has been reported in the literature in several individuals and in at least one family affected with Hereditary Breast and Ovarian Cancer (e.g. Balia 2010, Tung 2015, Sokolenko 2015, Susswein 2015, Sun 2017). These data indicate that the variant is very likely to be associated with disease. One study noted that the there was a differential expression of the WT and the mutated mRNA, presumably due to nonsense mediated decay (NMD), though no experimental data was provided (Balia 2010). Seven clinical diagnostic laboratories and one database (LOVD) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.