ClinVar

Description

The p.Ala1309Thr variant has been previously identified in association with breast cancer (Broeks 2008) However, a meta-analysis including the samples from Broeks et al and other breast cancer cohorts, found the p.Ala1309Thr variant in cases and controls at similar frequencies (Tavtigian 2009). This variant is listed in the NHLBI GO Exome Sequencing Project with an overall population frequency of 0.11 percent (identified on 14 out of 12998 chromosomes) and is listed in the Exome Aggregation Consortium Browser with an overall population frequency of 0.062 percent (identified on 75 out of 121298 chromosomes). The alanine at position 1309 is weakly conserved (considering 9 species, Alamut v.2.8.1) and computational analyses of the effects of the p.Ala1309Thr variant on protein structure and function provide conflicting results (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Ala1309Thr variant with certainty. Pathogenic variants in ATM are causative for ataxia-telangiectasia (MIM: 208900), and are inherited in autosomal recessive manner. This individual is at least a carrier of the p.Ala1309Thr variant. Deep intronic variants and variants in the untranslated region are not analyzed by this method, therefore, another pathogenic ATM variant cannot be ruled out. Classic ataxia-telangiectasia (A-T) is characterized by progressive cerebellar ataxia, telangiectases of the conjunctivae, frequent infections, sensitivity to ionizing radiation, and an increased risk for malignancy. Serum immunoglobulin deficiencies (decreased concentrations of IgA, IgG, with normal or elevated IgM), poor antibody response to pneumococcal polysaccharide vaccines, and T and B cell deficiencies are common in classic A-T.