As a group, women who carry germline mutations in PALB2 are at increased risk of breast cancer. Little is known about by how much, or whether risk differs by mutation or family history, due to the paucity of studies of cases unselected for family history.

We screened 1,403 case-probands participating in a population-based, age-at-onset-stratified study of Australian women with invasive breast cancer for PALB2 mutations. The age-specific risk of breast cancer was estimated from the cancer histories of first- and second-degree relatives of mutation carrying probands using a modified segregation analysis that included a polygenic modifier and conditioned on the carrier case proband. Further screening for PALB2 c.3113G>A (W1038X) was conducted for 779 multiple-case breast cancer families ascertained through family cancer clinics in Australia and New Zealand and 764 population-based controls.

We found five independent case probands in the population-based sample with the protein-truncating mutation PALB2 c.3113G>A (W1038X); two of 695 diagnosed before age 40 years and three of 708 diagnosed when aged 40-59 years. Both the two early-onset carrier case probands had very strong family histories of breast cancer. Further testing found that the mutation segregated with breast cancer in these families. No c.3113G>A (W1038X) carriers were found in 764 population-based unaffected controls. The hazard ratio was estimated to be 30.1 (95% CI 7.5 - 120; p < 0.0001) and the corresponding cumulative risk estimates were 49% (95% CI 15 - 93) to age 50 and 91% (95% CI 44 - 100) to age 70. We found a further eight families carrying this mutation in 779 multiple-case breast cancer families ascertained through family cancer clinics.

The PALB2 c.3113G>A mutation, appears to be associated with substantial risks of breast cancer that are of clinical relevance.

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