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Abstract

The susceptibility gene for ataxia telangiectasia, ATM, is also an intermediate-risk breast-cancer-susceptibility gene. However, the spectrum and frequency distribution of ATM mutations that confer increased risk of breast cancer have been controversial. To assess the contribution of rare variants in this gene to risk of breast cancer, we pooled data from seven published ATM case-control mutation-screening studies, including a total of 1544 breast cancer cases and 1224 controls, with data from our own mutation screening of an additional 987 breast cancer cases and 1021 controls. Using an in silico missense-substitution analysis that provides a ranking of missense substitutions from evolutionarily most likely to least likely, we carried out analyses of protein-truncating variants, splice-junction variants, and rare missense variants. We found marginal evidence that the combination of ATM protein-truncating and splice-junction variants contribute to breast cancer risk. There was stronger evidence that a subset of rare, evolutionarily unlikely missense substitutions confer increased risk. On the basis of subset analyses, we hypothesize that rare missense substitutions falling in and around the FAT, kinase, and FATC domains of the protein may be disproportionately responsible for that risk and that a subset of these may confer higher risk than do protein-truncating variants. We conclude that a comparison between the graded distributions of missense substitutions in cases versus controls can complement analyses of truncating variants and help identify susceptibility genes and that this approach will aid interpretation of the data emerging from new sequencing technologies.

Figures

Figure 1
Figure 1
Domain Organization of ATM and Case-Control Distribution of Missense Substitutions by Align-GVGD Grade (A) Distribution of rare C0, C15, and C25 missense substitutions superimposed on the domain organization of ATM. Note that if two distinct substitutions are located very close to each other, we shifted one by a few amino acids so that the presence of both is visible. (B) Distribution of rare C35, C45, C55, and C65 missense substitutions. We labeled the C65 missense substitutions falling from Ile1960 until the end of the protein. (C) Sequence-conservation profile across ATM. The fraction of invariant positions (GV = 0) across the ATM protein multiple sequence alignment was measured in a 20-residue sliding window. Results were smoothed by inclusion of (1/e × sequence invariance) in the ten residues preceding and trailing each window, then normalized. The analysis was repeated with the use of a conservation criterion of only conservative substitution or invariance (GV < 65) across species. Citations correspond to Fernandes et al., Lim et al., Shafman et al., and Khanna et al.
Figure 2
Figure 2
ATM Missense Substitutions Graded C65 by Align-GVGD and/or Scored 0.00 by SIFT Substitution designations are given over their respective positions in the ATM alignment. Amino acid symbols are colored to represent standard Dayhoff groupings. (A) Substitutions graded as C65; although most of these were scored 0.00 by SIFT, note that the last two fall at slightly variable positions and were scored as 0.01 by SIFT. “†” indicates that p.S2855R is the first substitution of the two-amino-acid substitution p.SV2855_2856RI. (B) Substitutions scored as 0.00 by SIFT but as C55 or lower by Align-GVGD.

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