ATM MUTATIONS AND PHENOTYPES IN ATAXIA-TELANGIECTASIA FAMILIES IN THEBRITISH-ISLES - EXPRESSION OF MUTANT ATM AND THE RISK OF LEUKEMIA, LYMPHOMA, AND BREAST-CANCER

We report the spectrum of 59 ATM mutations observed in ataxia-telangie ctasia (A-T) patients in the British Isles. Of 51 ATM mutations identi fied in families native to the British Isles, II were founder mutation s, and 2 of these 11 conferred a milder clinical phenotype with respec t to both cerebellar degeneration and cellular features. We report, in two A-T families, an ATM mutation (7271T --> G) that may be associate d with an increased risk of breast cancer in both homozygotes and hete rozygotes (relative risk 12.7; P = .0025), although there is a less se vere A-T phenotype in terms of the degree of cerebellar degeneration. This mutation (7271T --> G) also allows expression of full-length ATM protein at a level comparable with that in unaffected individuals. In addition, we have studied 18 A-T patients, in 15 families, who develop ed leukemia, lymphoma, preleukemic T-cell proliferation, or Hodgkin ly mphoma, mostly in childhood. A wide variety of ATM mutation types, inc luding missense mutations and in-frame deletions, were seen in these p atients. We also show that 25% of all A-T patients carried in-frame de letions or missense mutations, many of which were also associated with expression of mutant ATM protein.