# Challenging the extended phenotype: HRD-negative salivary gland carcinoma in a BRCA1 founder-variant carrier, case report and literature review

## TL;DR

A woman with a BRCA1 mutation developed a salivary gland tumor, but tests showed her cancer was not driven by BRCA1, challenging the idea that these tumors are part of hereditary cancer syndrome.

## Contribution

This is the first report of a BRCA1-associated salivary gland tumor with HRD testing, showing no HRD and challenging the link between BRCA1 and these tumors.

## Key findings

- The salivary gland tumor in a BRCA1 carrier showed no homologous recombination deficiency (HRD).
- The tumor had a BRCA1 variant and TP53 mutation but no loss of heterozygosity in BRCA1.
- These findings suggest salivary gland tumors in BRCA1 carriers may not be caused by BRCA1 dysfunction.

## Abstract

Pathogenic BRCA1 variants are established in hereditary breast and ovarian cancer (HBOC) and associated with pancreatic, prostate, and gastric cancers. Salivary gland tumors (SGTs) have been reported in BRCA1/2 carriers and suggested as part of an extended HBOC phenotype based on epidemiological associations. However, functional evidence is lacking, and homologous recombination deficiency (HRD)—the hallmark of BRCA-driven cancers—has not been systematically assessed in BRCA1-associated SGTs.

We report a Colombian family segregating the BRCA1 c.3331_3334delCAAG (p.Gln1111Asnfs*5) founder variant with phenotypic variability across four generations: gastric (31%), breast (37.5%), colorectal (19%), and thyroid cancers (12.5%). The proband, a 61-year-old woman, developed high-grade mucoepidermoid carcinoma of the parotid gland. Germline testing confirmed the familial BRCA1 variant. Tumor profiling revealed the same BRCA1 variant (VAF 56%) plus a pathogenic TP53 mutation (c.730G>T, p.Gly244Cys; VAF 32%), without BRCA1 loss of heterozygosity. HRD testing using shallow whole genome sequencing showed preserved homologous recombination function (Genomic Instability Score: 0.01, LGA: 11.40, LPC: 0), all below HRD-positive thresholds.

This represents the first SGT in a BRCA1 carrier evaluated with HRD testing. The absence of HRD argues against BRCA1-driven tumorigenesis despite clear familial segregation. These findings challenge the presumed causal relationship between BRCA1 variants and SGT development. Clinical implications are direct: SGTs in BRCA1 carriers should not be assumed eligible for PARP inhibitor therapy without HRD confirmation, and enhanced surveillance appears unwarranted. This case underscores that co-occurrence does not establish causation and highlights the critical importance of functional validation before expanding hereditary cancer spectra.