Comparative analysis of a founder BRCA2 double mutation versus single mutation carriers reveals no additional clinical risk.

BACKGROUND

Double mutations (DMs) in cis within the same BRCA gene are extremely rare, and their clinical significance remains uncertain, as it is unclear whether they confer an additive risk compared with single pathogenic variants (PVs).

MATERIALS AND

METHODS

We retrospectively analyzed a cohort of 1722 patients referred for suspected Hereditary Breast and Ovarian Cancer (HBOC). Among them, 9 unrelated probands were found to carry the same BRCA2 DM: c.631G>A (p.Val211Ile) in exon 7 and c.7008-2A>T (IVS13-2A>T) at the acceptor splice site of intron 13. Both variants were confirmed to co-segregate in cis. A control group of 19 probands with a single BRCA2 PV located between exons 7 and 14 was selected for comparison.

RESULTS

All DM families originated from the same geographic area in Southern Italy, suggesting a founder effect. The mean age at breast cancer onset was 50.7 years in the DM group and 51.4 years in the control group. Tumor spectrum and distribution among probands and relatives were comparable between groups, and BRCA2-related breast cancers were predominantly hormone receptor-positive in both cohorts. No statistically significant differences were observed regarding cancer types, stage, or receptor profile.

CONCLUSIONS

These findings suggest that the BRCA2 double mutation c.631G>A/c.7008-2A>T may have a founder effect, and the coexistence of the two variants does not appear to confer an additive cancer risk or a more severe clinical phenotype compared with carriers of a single BRCA2 pathogenic mutation.