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


Currently, the clinical applicability of CHEK mutations remains uncertain because of low mutation prevalence and lack of guidelines for clinical management.[35]


Ataxia telangiectasia (AT) (OMIM) is an autosomal recessive disorder characterized by neurologic deterioration, telangiectasias, immunodeficiency states, and hypersensitivity to ionizing radiation. It is estimated that 1% of the general population may be heterozygote carriers of ATM mutations (OMIM).[36] More than 300 mutations in the gene have been identified to date, most of which are truncating mutations.[37] ATM proteins have been shown to play a role in cell cycle control.[38,39,40] In vitro, AT-deficient cells are sensitive to ionizing radiation and radiomimetic drugs, and lack cell cycle regulatory properties after exposure to radiation.[41]

Initial studies searching for an excess of ATM mutations among breast cancer patients provided conflicting results, perhaps due to study design and mutation testing strategies.[42,43,44,45,46,47,48,49,50,51,52] However, two large epidemiologic studies have demonstrated a statistically increased risk of breast cancer among female heterozygote carriers, with an estimated RR of approximately 2.0.[52,53] Despite this convincing epidemiologic association, the clinical application of testing for ATM mutations is unclear due to the wide mutational spectrum and the logistics of testing. Because the presence of a mutation could pose a risk in screening-related radiation exposure, further investigation is needed.


BRIP1 (also known as BACH1) encodes a helicase that interacts with the BRCT domain of BRCA1. This gene also has a role in BRCA1-dependent DNA repair and cell cycle checkpoint function. Biallelic mutations in BRIP1 are a cause of Fanconi anemia,[54,55,56] much like such mutations in BRCA2. Inactivating mutations of BRIP1 are associated with an increased risk of breast cancer. In one study, more than 3,000 individuals from BRCA1/BRCA2 mutation negative families were examined for BRIP1 mutations. Mutations were identified in 9 of 1,212 individuals with breast cancer but in only 2 of 2,081 controls (P = .003). The RR of breast cancer was estimated to be 2.0 (95% confidence interval [CI], 1.2–3.2; P = .012). Of note, in families with BRIP1 mutations and multiple cases of breast cancer, there was incomplete segregation of the mutation with breast cancer, consistent with a low penetrance allele and similar to that seen with CHEK2.[57]


PALB2 (partner and localizer of BRCA2) interacts with the BRCA2 protein and plays a role in homologous recombination and double-stranded DNA repair. Similar to BRIP1 and BRCA2, biallelic mutations in PALB2 have also been shown to cause Fanconi anemia.[58] PALB2 mutations have been screened for in multiple small studies of familial and early-onset breast cancer in multiple populations.[59,60,61,62,63,64,65,66,67,68,69,70,71] Mutation prevalence has ranged from 0.4% to 3.4%. Similar to BRIP1 and CHEK2, there was incomplete segregation of PALB2 mutations in families with hereditary breast cancer.[60] Among 559 cases with contralateral breast cancer and 565 matched controls with unilateral breast cancer, pathogenic (truncating) PALB2 mutations were identified in 0.9% of cases and in none of the controls (RR, 5.3; 95% CI, 1.8–13.2).[71] A Finnish PALB2 founder mutation (c.1592delT) has been reported to confer a 40% risk of breast cancer to age 70 years [61] and is associated with a high incidence (54%) of triple-negative disease and lower survival.[62] Mutations have been observed in early-onset and familial breast cancer in many populations.[63,64]


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