ClinVar

Description

Variant summary: PALB2 c.315G>C (p.Glu105Asp) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251116 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.315G>C has been reported in the literature in individuals affected with Breast Cancer (e.g., Tischkowitz_2012, Krivokuca_2019), pancreatic cancer (e.g., Mizukami_2020), and ovarian cancer (e.g., Prokofyeva_2023, Krivokuca_2019). Additionally one Japanese case-control association study on 7,051 unselected breast cancer cases and 11,241 female controls showed no association of this variant with breast cancer along with a final assessment as benign (Momozawa_2018); conversely, another Japanese case-control study on 1,005 pancreatic cancer patients and 23,705 controls reported the variant with an odds ratio of 7.9 (95% CI: 0.8-44.1; Mizukami_2020). These reports do not provide unequivocal conclusions about association of the variant with PALB2-associated cancers. At-least one co-occurrence with another pathogenic variant has been reported (BRCA1 c.1054G>T, p.Glu352*) in a 46 year old with HBOC and a family history of breast cancer, providing supporting evidence for a benign role (Krivocuca_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30651582, 30287823, 22241545, 37013556, 28779002, 32980694). ClinVar contains an entry for this variant (Variation ID: 126718). Based on the evidence outlined above, the variant was classified as uncertain significance.