What question did this study set out to answer?

To determine the frequency and spectrum of pathogenic and likely pathogenic variants in non-BRCA genes among individuals with a history of breast or ovarian cancer.

April 23, 2026Open Access

High Prevalence of Non‐ BRCA Pathogenic Variants and a Recurrent PALB2 Variant in an Argentine Hereditary Breast and Ovarian Cancer Cohort

Key Points

To determine the frequency and spectrum of pathogenic and likely pathogenic variants in non-BRCA genes among individuals with a history of breast or ovarian cancer.
Retrospective analysis of 283 individuals tested between 2016-2022.
Utilized multigene next-generation sequencing panels and Sanger sequencing.
Evaluated variants based on contemporary clinical criteria.
Identified P/LPVs in 30% of the cohort, with 11.3% in non-BRCA genes.
PALB2 was the most prevalent non-BRCA gene variant identified at 4.59%.
Five unrelated families carried the recurrent PALB2 c.1653T>A variant, indicating a possible founder effect.

Abstract

Hereditary breast and ovarian cancer (HBOC) syndromes are strongly associated with germline pathogenic variants. While genetic testing historically focused on BRCA1/2, multigene panels have revealed clinically relevant variants in numerous non-BRCA genes. However, data on the spectrum and prevalence of these variants remain limited in Argentina, particularly in regions with distinctive admixture patterns. This study aimed to determine the frequency and spectrum of pathogenic and likely pathogenic variants (P/LPVs) in non-BRCA genes among patients with a personal and/or family history of breast or ovarian cancer evaluated in Córdoba, Argentina. We conducted a retrospective analysis of 283 individuals tested within the Oncogenetics Program at Hospital Privado Universitario de Córdoba between 2016 and 2022 using multigene next-generation sequencing panels and Sanger sequencing according to contemporary clinical criteria. P/LPVs were identified in 85 individuals (30.0%, 95% CI: 24.7-35.8), with non-BRCA genes accounting for 32 P/LPVs (11.3%, 95% CI: 7.9-15.6 of the cohort). The most prevalent non-BRCA genes were PALB2 (4.59%, 95% CI: 2.5-7.7) and CHEK2 (2.47%, 95% CI: 1.0-5.0), followed by TP53, MUTYH, and ATM. Notably, the PALB2 c.1653T>A variant was identified in five unrelated families, representing a recurrent variant compatible with a possible founder effect in this population. Overall, these findings highlight a substantial contribution of non-BRCA P/LPVs-particularly PALB2-in this Córdoba-based HBOC cohort. Post hoc analyses suggested sufficient statistical sensitivity to detect the observed differences; however, results should be interpreted considering the retrospective, single-center design. These findings support the clinical value of incorporating non-BRCA genes into multigene testing strategies in Argentina and underscore the need for larger multi-center studies to confirm these observations and refine genetic counseling and surveillance strategies in Latin American populations.

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Cite This Study

Martin et al. (Wed,) studied this question.

synapsesocial.com/papers/69e9b7c585696592c86eb5ed https://doi.org/https://doi.org/10.1002/cam4.71846

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