ClinVar

Description

Variant summary: PALB2 c.2379C>T alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a 5 donor site. However, these predictions have yet to be confirmed by functional studies. In contrast, one recently published functional study reported this variant among those with no impact on RNA splicing (Karam_2019). The authors considered the in-silico splicing predictions as a false positive evidence category and reported re-classifying this variant from a VUS to likely benign based on their study. The variant allele was found at a frequency of 7.4e-05 in 256744 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PALB2 causing Hereditary Breast And Ovarian Cancer Syndrome (7.4e-05 vs 0.00016), allowing no conclusion about variant significance. c.2379C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Catucci_2014, Damiola_2015, Thompson_2015, Borecka_2016, Decker_2017 etc.). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. In addition, this variant was found in four women in FLOSSIES database of cancer free women older than age 70, suggesting that the variant could be benignTo our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 12 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar classified as VUS (n=5), Likely Benign (n=6) and Benign (n=1). Based on the evidence outlined above, the variant was classified as benign.