The ATM gene was identified as a breast cancer risk gene on chromosome 11 in 1991 (Swift 1991). Deleterious germline mutations in ATM have primarily been associated with an increased risk of breast cancer (Tavtigian 2009, Thompson 2005, van Os 2016). ATM mutations have also been associated with an increased risk of pancreatic cancer (Roberts 2012, Grant 2015), colorectal cancer (Thompson 2005), and gastric cancer (Thompson 2005, Helgason 2015).
Individuals with biallelic (homozygous or compound heterozygous) mutations in ATM typically present with ataxia-telangiectasia, an autosomal recessive disorder characterized by cerebellar degeneration, immunodeficiency, chromosomal instability, radiosensitivity, and cancer predisposition (Concannon 1997, Gilad 1998).
Affected Phenotypes Included in Penetrance Model
Breast Cancer (male and female)
Note: Cancers other than breast cancer, such as pancreatic cancer, colorectal cancer, ovarian cancer, and stomach cancer, are not included in this model.
Coding the Pedigree
Code affected individuals in column 5 of the Excel or plain text file used to build your pedigree.
- Code “2” (affected) for individuals with breast cancer.
- Code “1” (unaffected) for individuals who have not had breast cancer.
- Code “0” for individuals with uncertain or unknown affected status.
More information on formatting pedigrees can be found here.
Penetrance classes for ATM
Penetrance is gender specific.
|Age Range||Homozygous Normal||Heterozygous||Homozygous Normal||Heterozygous|
- Swift M, et al. Incidence of cancer in 161 families affected by ataxia-telangiectasia. N Engl J Med. 1991, 325:1831. PMID: 1961222
- Tavtigian SV, et al. Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer. Am J Hum Genet. 2009, 85:427. PMID: 19781682
- Thompson D, et al. Cancer risks and mortality in heterozygous ATM carriers. J Natl Cancer. 2005, 97:813. PMID: 15928302
- van Os NJH, et al. Health risks for ataxia-telangiectasia mutated heterozygotes: a systematic review, meta-analysis and evidence-based guideline. Clin Genet. 2016, 90:105. PMID: 26662178
- Roberts NJ, et al. ATM mutations in patients with hereditary pancreatic cancer. Cancer Discov. 2012, 2:41. PMID: 22585167
- Grant RC, et al. Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer. Gastroenterology. 2015, 148:556. PMID: 25479140
- Helgason H, et al. Loss-of-function variants in ATM confer risk of gastric cancer. Nat Genet. 2015, 47:906. PMID: 26098866
- Concannon P, et al. Diversity of ATM gene mutations detected in patients with ataxia-telangiectasia. Hum Mutat. 1997, 10:100. PMID: 9259193
- Gilad S, et al. Genotype-phenotype relationships in ataxia-telangiectasia and variants. Am J Hum Genet. 1998, 62:551. PMID: 9497252
- Marabelli, M., Cheng, S., Parmigiani, G. Penetrance of ATM gene mutations in breast cancer: A meta‐analysis of different measures of risk. Genet. Epidemiol. 2016, 40: 425. doi:10.1002/gepi.21971 PMID:27112364