Characterization ofATM mutations in 41 Nordic families with Ataxia Telangiectasia

Abstract

The Ataxia Telangiectasia Mutation (ATM) gene is mutated in the rare recessive syndrome Ataxia Telangiectasia (AT), which is characterized by cerebellar degeneration, immunodeficiency, and cancer predisposition. In this study, 41 AT families from Denmark, Finland, Norway, and Sweden were screened for ATM mutations. The protein truncation test (PTT), fragment length and heteroduplex analyses of large (0.8–1.2 kb) cDNA fragments were used. In total, 67 of 82 (82%) of the disease‐causing alleles were characterized. Thirty‐seven unique mutations were detected of which 25 have not previously been reported. The mutations had five different consequences for the ATM transcript: mutations affecting splicing (43%); frameshift mutations (32%); nonsense mutations (16%); small in‐frame deletions (5%); and one double substitution (3%). In 28 of the probands mutations were found in both alleles, in 11 of the probands only one mutated allele was detected, and no mutations were detected in two Finnish probands. One‐third of the probands (13) were homozygous, whereas the majority of the probands (26) were compound heterozygote with at least one identified allele. Ten alleles were found more than once; one Norwegian founder mutation constituted 57% of the Norwegian alleles. Several sequence variants were identified, none of them likely to be disease‐causing. Some of them even involved partial skipping of exons, leading to subsequent truncation of the ATM protein. Hum Mutat 16:232–246, 2000. © 2000 Wiley‐Liss, Inc.

Association of common ATM polymorphism with bilateral breast cancer

“…7 We have previously analyzed cases of 162 families displaying signs of hereditary susceptibility to breast cancer for the occurrence of ATM germline mutations originally identified in Finnish A-T families. 8,9 Of 8 different A-T-related mutations, only 6903insA (leading to stop at codon 2372) and 7570G?C (Ala2524Pro) were associated with increased breast cancer risk. However, the overall frequency of these 2 mutations was low, as 6903insA was observed no more than in 1 and 7570G?C in 2 families.…”

Association of common ATM polymorphism with bilateral breast cancer

“…7 We have previously analyzed cases of 162 families displaying signs of hereditary susceptibility to breast cancer for the occurrence of ATM germline mutations originally identified in Finnish A-T families. 8,9 Of 8 different A-T-related mutations, only 6903insA (leading to stop at codon 2372) and 7570G?C (Ala2524Pro) were associated with increased breast cancer risk. However, the overall frequency of these 2 mutations was low, as 6903insA was observed no more than in 1 and 7570G?C in 2 families.…”

Delineation of the Role of the Mre11 Complex in Class Switch Recombination

“…The serum levels of immunoglobulin classes and IgG subclasses were measured using nephelometry. The genetic characterization and immunoglobulin levels in the A-T and NBS patients have been described previously (19,39,40). Patients with "idiopathic" IgA deficiency (IgAD) have also been described previously (19).…”

Functional and computational assessment of missense variants in the ataxia-telangiectasia mutated (ATM) gene: mutations with increased cancer risk

“…Taken together, we estimate the frequency of operationally deleterious ATM missense mutations in A-T patients to comprise less than 10% of all known mutations. This is in stark contrast to the much greater frequency of ATM missense variants reported in breast cancer patients, and provides additional support for the hypothesis that missense variants in the ATM gene are associated primarily with a cancer phenotype rather than with a neurological impairment (Vorechovsky et al, 1996; Gatti et al, 1999; Laake et al, 2000; Chenevix-Trench et al, 2002; Concannon, 2002; Bernstein et al, 2003; Buzin et al, 2003; Sommer et al, 2003; Bernstein et al, 2006; Renwick et al, 2006). On the other hand, most missense variants (for all large genes) have not been operationally categorized as “deleterious” or “neutral”, so it is difficult to assess their disease-causing roles.…”

Association of common ATM polymorphism with bilateral breast cancer

“…7 We have previously analyzed cases of 162 families displaying signs of hereditary susceptibility to breast cancer for the occurrence of ATM germline mutations originally identified in Finnish A-T families. 8,9 Of 8 different A-T-related mutations, only 6903insA (leading to stop at codon 2372) and 7570G?C (Ala2524Pro) were associated with increased breast cancer risk. However, the overall frequency of these 2 mutations was low, as 6903insA was observed no more than in 1 and 7570G?C in 2 families.…”

Delineation of the Role of the Mre11 Complex in Class Switch Recombination

“…The serum levels of immunoglobulin classes and IgG subclasses were measured using nephelometry. The genetic characterization and immunoglobulin levels in the A-T and NBS patients have been described previously (19,39,40). Patients with "idiopathic" IgA deficiency (IgAD) have also been described previously (19).…”

Functional and computational assessment of missense variants in the ataxia-telangiectasia mutated (ATM) gene: mutations with increased cancer risk

“…Taken together, we estimate the frequency of operationally deleterious ATM missense mutations in A-T patients to comprise less than 10% of all known mutations. This is in stark contrast to the much greater frequency of ATM missense variants reported in breast cancer patients, and provides additional support for the hypothesis that missense variants in the ATM gene are associated primarily with a cancer phenotype rather than with a neurological impairment (Vorechovsky et al, 1996; Gatti et al, 1999; Laake et al, 2000; Chenevix-Trench et al, 2002; Concannon, 2002; Bernstein et al, 2003; Buzin et al, 2003; Sommer et al, 2003; Bernstein et al, 2006; Renwick et al, 2006). On the other hand, most missense variants (for all large genes) have not been operationally categorized as “deleterious” or “neutral”, so it is difficult to assess their disease-causing roles.…”

Association of common ATM polymorphism with bilateral breast cancer

“…7 We have previously analyzed cases of 162 families displaying signs of hereditary susceptibility to breast cancer for the occurrence of ATM germline mutations originally identified in Finnish A-T families. 8,9 Of 8 different A-T-related mutations, only 6903insA (leading to stop at codon 2372) and 7570G?C (Ala2524Pro) were associated with increased breast cancer risk. However, the overall frequency of these 2 mutations was low, as 6903insA was observed no more than in 1 and 7570G?C in 2 families.…”

Delineation of the Role of the Mre11 Complex in Class Switch Recombination

“…The serum levels of immunoglobulin classes and IgG subclasses were measured using nephelometry. The genetic characterization and immunoglobulin levels in the A-T and NBS patients have been described previously (19,39,40). Patients with "idiopathic" IgA deficiency (IgAD) have also been described previously (19).…”

Functional and computational assessment of missense variants in the ataxia-telangiectasia mutated (ATM) gene: mutations with increased cancer risk

“…Taken together, we estimate the frequency of operationally deleterious ATM missense mutations in A-T patients to comprise less than 10% of all known mutations. This is in stark contrast to the much greater frequency of ATM missense variants reported in breast cancer patients, and provides additional support for the hypothesis that missense variants in the ATM gene are associated primarily with a cancer phenotype rather than with a neurological impairment (Vorechovsky et al, 1996; Gatti et al, 1999; Laake et al, 2000; Chenevix-Trench et al, 2002; Concannon, 2002; Bernstein et al, 2003; Buzin et al, 2003; Sommer et al, 2003; Bernstein et al, 2006; Renwick et al, 2006). On the other hand, most missense variants (for all large genes) have not been operationally categorized as “deleterious” or “neutral”, so it is difficult to assess their disease-causing roles.…”