Table 4

Known PALB2 splice site variants for which we put a warning

Splicing siteVariant reporteddbSNPClinVarProposed
ClassificationReview statusAssertion method
E2 acceptorc.49-2A>Trs786203245Likely pathogenic**Ambry autosomal dominant
Invitae Variant Classification Sherlock
Uncertain significance
E5 acceptorc.1685-2A>Grs754660432Likely pathogenic**GeneDx variant classification
Ambry autosomal dominant
c.1685–1G>Crs1057520645Pathogenic*GeneDx variant classification
E7 acceptorc.2587-2A>Crs1060502787Likely pathogenic*Invitae Variant Classification Sherlock
E10 acceptorc.2997-2A>CLikely 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classification is based on splicing assays, and/or in segregation information supporting pathogenicity (Tina Pesaran, unpublished data; Kathleen S Hruska, unpublished data, Inviate ClinVar summary evidences).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.