Abstract Purpose: To characterize the prevalence of germline pathogenic or likely pathogenic (PLP) variants in Fanconi Anemia (FA) pathway genes among patients with invasive breast cancer (IBC) and evaluate opportunities for clinical actionability through germline and somatic analysis. Background: Disruption of the FA DNA repair pathway can impair homologous recombination (HR). While high-penetrance PLP variants in BRCA1, BRCA2, and PALB2 are established breast cancer susceptibility genes and contribute to HR deficiency (HRD), the clinical consequences of other FA germline PLP variants remain unclear. Using the updated cohort from the City of Hope INSPIRE Study, we assessed the prevalence and functional impact of germline PLP variants in 17 FA pathway genes. HRD, mutational signatures, and loss of heterozygosity were used to evaluate effects on HR integrity. These findings may have implications for HRD-related precision therapeutic intervention and clinical trial eligibility. Methods: This retrospective study included consented patients with histologically confirmed IBC enrolled in the INSPIRE Study as of January 14, 2025. Germline sequencing of 155 cancer predisposition genes was performed; patients with multiple FA variants were classified according to the FA gene of the highest penetrance. A cohort subset underwent paired tumor-normal whole exome sequencing (400x tumor, 180x normal), including HRD scoring (scarHRD), LOH determination, and SBS3 assessment (SigProfiler). Clinical data were obtained from cancer registries and medical records. Clinical trial eligibility criteria were evaluated using ClinicalTrials.gov. Results: Of 8,242 patients with IBC, 7,982 underwent germline sequencing; 592 (7.4%) had a PLP variant in an FA gene, including 197 (33.3%) in non-high-penetrance (non-HP) genes. Among 1,833 patients with paired tumor-normal sequencing, 145 (7.9%) had an FA PLP variant, of which 53 (2.89%) were in non-HP genes. HRD scores were ≥42 in 45.3% of non-HP carriers (Table 1). 24 of 53 patients (45.3%) with a non-HP FA germline PLP variant had HRD-positive (≥42) tumors. HRD-positivity is more likely among patients with germline PLP variants in non-HP FA pathway genes compared to those without a variant in any FA gene (RR 1.51, 95% CI 1.12 to 2.05; p 0.0077). Stage data were available for 1,548 patients; 128 (8.3%) were stage IV at diagnosis, including 7/128 (5.5%) with non-HP FA gene PLP variants. Conclusion: Germline PLPs in non-HP FA genes are present in a meaningful subset of patients with IBC and may be functionally relevant. These findings support the value of expanded germline testing and trial eligibility criteria that encompass the broader FA pathway and suggest that non-HP FA gene variants may serve as biomarkers for identifying patients likely to benefit from HRD-targeted therapies. Citation Format: L. Naghi, K. G. Roth, S. Lindsey, A. Seuylemezian, J. Bonner, L. Kruper, S. B. Gruber, J. Mortimer, K. McDonnell. Lower Penetrance Germline Fanconi Anemia Variants in Breast Cancer: Opportunities for Expanded Genetic Testing and Therapeutic Targeting in the Updated INSPIRE Study Cohort abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-01-27.
Naghi et al. (Tue,) studied this question.