Known PALB2 splice site variants for which we put a warning
| Splicing site | Variant reported | dbSNP | ClinVar | Proposed ACMG-AMP-2015 classification | ||
| Classification | Review status | Assertion method | ||||
| E2 acceptor | c.49-2A>T | rs786203245 | Likely pathogenic | ** | Ambry autosomal dominant Invitae Variant Classification Sherlock | Uncertain significance |
| E5 acceptor | c.1685-2A>G | rs754660432 | Likely pathogenic | ** | GeneDx variant classification Ambry autosomal dominant | |
| c.1685–1G>C | rs1057520645 | Pathogenic | * | GeneDx variant classification | ||
| E7 acceptor | c.2587-2A>C | rs1060502787 | Likely pathogenic | * | Invitae Variant Classification Sherlock | |
| E10 acceptor | c.2997-2A>C | – | Likely pathogenic | * | Ambry autosomal dominant | |
These five PALB2 variants are classified as pathogenic/likely pathogenic based on assertion criteria defined by the submitters. Ambry Genetics and/or GeneDx classify the indicated variants as pathogenic based on the fact that these are very rare variants located at canonical splice sites, predicted to abolish or significantly reduce native site using in silico predictors and identified in affected/+family history cohort. Invitae classifies the indicated variants as likely pathogenic based on the fact that donor and acceptor splice site variants are typically loss-of-function and loss-of-function variants in PALB2 are known to be pathogenic. Remarkably, for any of these variants classification is based on splicing assays, and/or in segregation information supporting pathogenicity (Tina Pesaran, unpublished data; Kathleen S Hruska, unpublished data, Inviate ClinVar summary evidences). These are splice site variants targeting acceptor sites for which, in our opinion (table 3), PVS1 is not necessarily warranted. For that reason, we propose that, in absence of functional and/or genetic data, these variants should be classified according to the ACMG-AMP-2015 guidelines as uncertain significance.
ACMG-AMP, American College of Medical Genetics and Genomics-Association for Molecular Pathology.