Variants in the ATM Gene Associated with a Reduced Risk of Contralateral Breast Cancer

DOI: 10.1158/0008-5472.CAN-08-0134 Published August 2008

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Figure 1.
Distribution of ATM variants (n = 240) in the WECARE Study population.

Table 1.

Risk of developing second primary breast cancer associated with ATM gene carrier status

ATM variants classification	Cases (n)	Controls (n)	Rate ratio * (95% CI)
Overall
Wild-type	271	480	1.0
Carrier of any ATM variant	437	917	0.8 (0.7–1.0)
Common ^†
Wild-type	271	480	1.0
Carrier of any common ATM variant	355	778	0.8 (0.6–0.9)
Rare ^†
Wild-type	271	480	1.0
Carrier of any rare ATM variant	148	264	1.0 (0.8–1.4)

↵* Adjusted for exact age at diagnosis of the first primary and countermatching weight. Common and rare models also adjusted for carriers of other remaining ATM variants.
↵† Common variants are defined as those carried by ≥1% of the WECARE Study participants. Rare variants are those carried by <1% of the participants.

Table 2.

Risk of developing second primary breast cancer associated with rare ATM variants

ATM variant classification	Cases (n)	Controls (n)	Rate ratio * (95% CI)
A-T–causing mutations
Wild-type	271	480	1.0
A-T–causing ^†	14	13	1.4 (0.6–3.4)
Variants of unknown effect classified by SIFT ^‡
Wild-type	271	480	1.0
Deleterious	39	56	1.3 (0.8–2.2)
Tolerated	36	72	0.9 (0.6–1.4)

↵* Adjusted for exact age at diagnosis of the first primary, countermatching weight and for carriers of the other remaining ATM variants.
↵† Meeting one or more of the following criteria: (a) changes predicted to result in truncation of the ATM protein whether by direct termination or frameshifting, (b) changes affecting the two highly conserved nucleotides flanking exons that direct splicing, (c) changes predicted to result in amino acid substitutions for which there is documented evidence of both a deleterious effect on ATM function and identification in diagnosed A-T patients, or (d) changes documented as A-T–causing in the ATM Mutation Database.
↵‡ Defined by SIFT. Variants with normalized probabilities <0.05 are predicted to be deleterious, whereas those ≥0.05 are predicted to be tolerated. Results for missense variants are adjusted for other variants.

Table 3.

Risk of developing second primary breast cancer associated with common ATM variants

Variant *	Effect	dbSNP ^†	Cases, n (%)	Controls, n (%)	Rate ratio ^‡ (95% CI)
c.378T>A	p.Asp126Glu	rs2234997	8 (1.1)	17 (1.1)	0.7 (0.2–2.0)
c.735C>T	Silent	rs3218674	21 (3.0)	40 (2.8)	1.0 (0.6–1.9)
c.1899-55T>G	Silent	rs4987943	34 (4.8)	121 (9.5)	0.5 (0.3–0.8)
c.2119T>C	p.Ser707Pro	rs4986761	20 (2.8)	30 (3.0)	1.0 (0.5–1.9)
c.2572T>C	p.Phe858Leu	rs1800056	14 (2.0)	42 (2.7)	0.5 (0.2–1.0)
c.3161C>G	p.Pro1054Arg	rs1800057	23 (3.2)	64 (4.7)	0.5 (0.3–0.9)
c.3285-10delT	Silent		8 (1.1)	15 (1.1)	0.8 (0.3–2.0)
c.4258C>T	p.Leu1420Phe	rs1800058	24 (3.4)	47 (3.4)	0.8 (0.4–1.4)
c.4578C>T	Silent	rs1800889	52 (7.3)	121 (9.0)	0.7 (0.5–1.1)
c.5497-8T>C	Silent	rs3092829	37 (5.2)	69 (4.9)	0.9 (0.5–1.4)
c.5557G>A	p.Asp1853Gln	rs1801516	173 (24.4)	339 (24.5)	0.9 (0.7–1.1)
c.5558A>T	p.Asp1853Val	rs1801673	4 (0.6)	30 (2.6)	0.2 (0.1–0.6)
c.5762+27G>A	Silent	rs3218673	8 (1.1)	22 (1.5)	0.6 (0.2–1.6)
c.6348-54T>C	Silent		3 (0.4)	19 (1.5)	0.2 (0.1–0.8)
c.8786+8A>C	Silent		39 (5.5)	99 (6.3)	0.7 (0.4–1.1)

NOTE: Variants carried by >1% of the WECARE Study subjects.
↵* Variants indicated relative to the reference sequence for the ATM Mutation Database (http://chromium.liacs.nl/lovd/refseq/ATM_codingDNA.html). Nomenclature as recommended by the Human Variome Project.
↵† rs numbers are provided for those SNPs currently listed in dbSNP.
↵‡ Adjusted for exact age at diagnosis of the first primary, countermatching weight, and for carriers of the other remaining ATM variants so that the rate ratio is relative to those for wild-type for ATM variants.