Abstract
IntroductionPALB2 is emerging as a high-penetrance breast cancer predisposition gene in the order of BRCA1 and BRCA2. However, large studies that have evaluated the full gene rather than just the most common variants in both cases and controls are required before all truncating variants can be included in familial breast cancer variant testing.MethodsIn this study we analyse almost 2000 breast cancer cases sourced from individuals referred to familial cancer clinics, thus representing typical cases presenting in clinical practice. These cases were compared to a similar number of population-based cancer-free controls.ResultsWe identified a significant excess of truncating variants in cases (1.3 %) versus controls (0.2 %), including six novel variants (p = 0.0001; odds ratio (OR) 6.58, 95 % confidence interval (CI) 2.3–18.9). Three of the four control individuals carrying truncating variants had at least one relative with breast cancer. There was no excess of missense variants in cases overall, but the common c.1676A > G variant (rs152451) was significantly enriched in cases and may represent a low-penetrance polymorphism (p = 0.002; OR 1.24 (95 % CI 1.09–1.47).ConclusionsOur findings support truncating variants in PALB2 as high-penetrance breast cancer susceptibility alleles, and suggest that a common missense variant may also lead to a low level of increased breast cancer risk.
Highlights
Partner and localizer of BRCA2 (PALB2) is emerging as a high-penetrance breast cancer predisposition gene in the order of BRCA1 and BRCA2
Further studies have identified a spectrum of truncating variants among breast cancer cases [7,8,9,10], the collective frequency of which has not been compared to Australian controls
Samples for mutation analysis Cancer-affected women in the study were referred by their physician to a specialist Familial Cancer Centre (FCC) for genetic testing of BRCA1 and BRCA2 between 1997 and 2014, and were identified as being at “high risk” of carrying a predisposing allele
Summary
PALB2 is emerging as a high-penetrance breast cancer predisposition gene in the order of BRCA1 and BRCA2. Large studies that have evaluated the full gene rather than just the most common variants in both cases and controls are required before all truncating variants can be included in familial breast cancer variant testing. In Australia, early studies identified PALB2 c.3113G > A (p.Trp1038*) as a recurring truncating mutation among familial breast cancer index cases, and established the enrichment of c.3113G > A in cases compared to controls [6]. Because early studies focused on screening just for the presumed common pathogenic mutations, in Australia (eviQ Cancer Treatments Online; [11]) it is not recommended to test for PALB2 truncating mutations aside from the recurring c.3113G > A variant, it is likely that all truncating
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