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Low- and Moderate-Penetrance Genes Associated With Breast and / or Ovarian Cancer


Male breast cancer has been observed in PALB2 mutation–positive breast cancer families.[59,65] In a study of 115 male breast cancer cases in which 18 men had BRCA2 mutations, an additional two men had either a pathogenic or predicted pathogenic PALB2 mutation (accounting for about 10% of germline mutations in the study and 1%–2% of the total sample).[59] Following the identification of PALB2 mutations in pancreatic tumors and the detection of germline mutations in 3% of 96 familial pancreatic patients,[72] numerous studies have pointed to a role for PALB2 in pancreatic cancer. A sixfold increase in pancreatic cancer was observed in the relatives of 33 BRCA1/2-negative, PALB2 mutation–positive breast cancer probands.[65]PALB2 mutations were detected in 3.7% of 81 familial pancreatic cancer families [73] and in 2.1% of 94 BRCA1/2 mutation–negative breast cancer patients who had either a personal or family history of pancreatic cancer.[74] Two relatively small studies, one of 77 BRCA1/2 mutation–negative probands with a personal or family history of pancreatic cancer, one-half of whom were of Ashkenazi Jewish descent, and another study of 29 Italian pancreatic cancer patients with a personal or family history of breast or ovarian cancer, failed to detect any PALB2 mutations.[75,76]

The observed prevalence of PALB2 mutations in familial breast cancer varied depending on ascertainment relative to personal and family history of pancreatic and ovarian cancers, but in all studies, the observed mutation rate was less than 4%. The RR of breast cancer appears moderate, and the risk of other cancers (e.g., pancreatic) is poorly defined; therefore, the clinical utility of testing is not clear. There is insufficient evidence to support routine screening of PALB2 when tests of the more common genes, namely BRCA1/2, are negative.


The Breast Cancer Association Consortium (BCAC) investigated single nucleotide polymorphisms identified in previous studies as possibly associated with excess breast cancer risk in 15,000 to 20,000 cases and 15,000 to 20,000 controls. Two SNPs, CASP8 D302H and TGFB1 L10P, were associated with invasive breast cancer with RRs of 0.88 (95% CI, 0.84–0.92) and 1.08 (95% CI, 1.04–1.11), respectively.[77]


RAD51 and the family of RAD51-related genes, also known as RAD51 paralogs, are thought to encode proteins that are involved in DNA damage repair through homologous recombination and interaction with numerous other DNA repair proteins, including BRCA1 and BRCA2. RAD51 protein plays a central role in single-strand annealing in the DNA damage response. RAD51 recruitment to break sites and recombinational DNA repair depend on the RAD51 paralogs, although their precise cellular functions are poorly characterized.[78] Mutations in these genes are thought to result in loss of RAD51 focus formation in response to DNA damage.[79]


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