Currently, the clinical applicability of CHEK mutations remains uncertain because of low mutation prevalence and lack of guidelines for clinical management.
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). More than 300 mutations in the gene have been identified to date, most of which are truncating mutations. 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.
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.
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. 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. 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). A Finnish PALB2 founder mutation (c.1592delT) has been reported to confer a 40% risk of breast cancer to age 70 years  and is associated with a high incidence (54%) of triple-negative disease and lower survival. Mutations have been observed in early-onset and familial breast cancer in many populations.[63,64]