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Germline ATRIP variants have recently been implicated in inherited breast cancer risk based on exome sequencing and large population cohorts. In a Polish familial breast cancer study, the truncating variant c.1153G>T (p.Gly385Ter) was identified in two affected women and subsequently observed in 42 of 16,085 unselected breast cancer cases versus 11 of 9,285 controls (OR = 2.14, 95% CI 1.13–4.28, p = 0.02) (PMID:36977412). In the UK Biobank, ATRIP loss-of-function alleles were detected in 13 of 15,643 breast cancer cases compared to 40 of 157,943 controls (OR = 3.28, 95% CI 1.76–6.10, p < 0.001) (PMID:36977412).
These findings support an autosomal dominant predisposition model for ATRIP-related breast cancer. No formal familial segregation data have been reported. The variant spectrum is dominated by premature termination alleles predicted to abolish ATRIP function.
Functional studies showed that the p.Gly385Ter allele is weakly expressed and fails to support ATRIP’s role in the replication stress response. Tumors from variant carriers exhibit loss of heterozygosity at the ATRIP locus and homologous recombination deficiency, linking ATRIP haploinsufficiency to genomic instability in breast epithelium.
ATRIP encodes the essential partner of ATR kinase at stalled replication forks, mediating the DNA damage checkpoint. Haploinsufficiency of ATRIP compromises replication fork stability and fosters DNA damage accumulation, a key mechanism in breast tumorigenesis.
The convergence of significant case-control burden across >55 probands with ATRIP loss-of-function variants and concordant functional impairment fulfills ClinGen strong criteria for breast cancer predisposition. Further replication in diverse populations will refine penetrance estimates.
Key take-home: Heterozygous ATRIP loss-of-function variants confer a significant increase in breast cancer risk through defective replication stress response and genome maintenance.
Gene–Disease AssociationStrongSignificant burden of ATRIP loss-of-function variants in three cohorts (42/16,085 vs 11/9,285; 13/15,643 vs 40/157,943) with ORs 2.14 and 3.28, plus LOH and HR deficiency in tumors Genetic EvidenceModerateAggregate of 55 breast cancer cases with germline ATRIP truncating variants across case-control and population-based studies Functional EvidenceModerateTruncated ATRIP shows reduced expression, failure to respond to replication stress, and tumor assays reveal LOH and homologous recombination deficiency |