ATM is a gene classically associated with an autosomal recessive condition called ataxia-telangiectasia (AT). AT is an autosomal recessive disorder characterized by progressive cerebellar ataxia with onset between ages one and four, telangiectases of the conjunctivae, oculomotor apraxia, immune defects, and a predisposition to malignancy, particularly leukemia and lymphoma.  Heterozygous carrier females also have an estimated 2-4 fold increased risk for breast cancer.⁷

BARD1, BRIP1, MRE11A, NBN, RAD50, and RAD51C are genes involved in the Fanconi anemia (FA)–BRCA pathway, which is critical for DNA repair by homologous recombination and interact in vivo with BRCA1 and/or BRCA2.^3,8-10 Mutations in these genes are estimated to confer up to a 4 fold increase in breast cancer risk, and mutations in each have been reported in at least 1 identified case of ovarian cancer to date.¹¹

CHEK2 is a gene that receives signals from damaged DNA, transmitted to CHEK2 via ATM.  Known substrates of CHEK2 include BRCA1, BRCA2 and TP53, which have all been implicated in cellular processes responsible for the maintenance of genomic stability. Multiple studies indicate that mutations in the CHEK2 gene confer an increased risk of developing many types of cancer including breast, prostate, colon, thyroid, and kidney. Mutations are more likely to be found among women with bilateral versus those with unilateral breast cancers. A female carrier of a CHEK2 mutation has approximately a 2 fold increase in lifetime breast cancer risk and has a 1% risk per year of developing a second breast primary cancer. Ovarian cancer risk has also been suggested.^11-15

CDH1 germline mutations have been associated with hereditary diffuse gastric cancer (HDGC) and lobular breast cancer in women. In one published study, the estimated cumulative risk of gastric cancer for CDH1 mutation carriers by age 80 years is 67% for men and 83% for women.¹⁶ HDGC patients typically present with diffuse-type gastric cancer with signet ring cells diffusely infiltrating the wall of the stomach and, at late stage, linitis plastica. An elevated risk of lobular breast cancer is also associated with HDGC,¹⁷ with an estimated lifetime breast cancer risk of 39-52%.

MUTYH germline mutations are classically associated with an autosomal recessive form of hereditary polyposis. Clinical studies have shown that MUTYH mutations were detected in 33% and 57% of patients with clinical familial adenomatous polyposis (FAP)and attentuated familial adenomatous polyposis (AFAP), respectively, who are negative for mutations in the APC gene.¹⁸ Two common mutations, p.Y179C and p.G396D (originally designated as p.Y165C and p.G382D), have been reported as homozygous or compound heterozygous in about 70%-86% of MAP patients.^19,20 Heterozygous mutations have also been associated with a 1.9 fold increased risk for breast cancer.²¹ In this series, characteristics of tumors and at of diagnosis in carriers with MUTYH variants were similar to those without MUTYH variants.^18-21

PALB2 germline mutations have been associated with increased risk for pancreatic cancer, breast cancer, and fanconi-anemia complementation group N (FA-N). Familial pancreatic and/or breast cancer due to PALB2 mutations is inherited in an autosomal dominant pattern, while FA-N is an autosomal recessive condition.  Females with a PALB2 mutation have a 2 to 4 fold increase in risk for breast cancer,^22-24 and a recent report has suggested an increased risk for ovarian cancer as well.¹¹

PTEN is a gene that has been associated with Cowden syndrome, PTEN Hamartoma Tumor syndrome (PHTS), Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome and autism spectrum disorder. Cowden Syndrome is a multiple hammartoma syndrome with a high risk of developing tumors of the thyroid, breast, and endomentrium. Mucocutaneous lesions, thyroid abnormalities, fibrocystic disease, multiple uterine leiomyoma, and macrocephaly can also be seen. Affected individuals have a lifetime risk of up to 50% for breast cancer, 10% for thyroid cancer, and 5-10% for endometrial cancer. Over 90% of individuals with CS will express some clinical manifestation by their 20’s.^25,26

STK11 germline mutations have been associated with Peutz-Jegher syndrome (PJS), an autosomal dominant disorder characterized by the development of gastrointestinal hamartomatous polyps and melanin hyperpigmentation of the skin and mucous membranes. Overall, individuals affected with PJS have a 57-81% risk of developing cancer by age of 70, with gastrointestinal/colon and breast cancers being the most common.^27,28

TP53 is a tumor suppressor gene that causes Li-Fraumeni and Li-Fraumeni like syndrome, which can affect adults and children. Individuals with TP53 mutations have a 50% risk of developing any of the associated cancers by age 30 and a lifetime risk up to 90%, including sarcomas, breast cancer, brain tumors (including astrocytomas, glioblastomas, medulloblastomas and choroid plexus carcinomas), and adrenocortical carcinoma (ACC). Studies have shown that a small percentage of women who are BRCA1 and BRCA2 negative are identified to have mutations in TP53.^15,29,30