Hereditary Ovarian Cancer Genes Found Beyond Traditionally High-Risk Groups

Germline pathogenic variants (gPVs) occur in a subset of patients with ovarian cancer, with the highest prevalence among those with Ashkenazi Jewish ancestry, followed by Asian and Hispanic patients, supporting recommendations for inclusive testing.¹

Genetic Drivers of Hereditary Ovarian Cancer

The study published in Gynecologic Oncology reported that 15% to 20% of ovarian cancer cases are attributable to hereditary cancer syndromes, with gPVs in BRCA1 and BRCA2 accounting for 65% to 85% of these cases. Other genes implicated in hereditary ovarian cancer include homologous recombination (HR) repair genes, such as RAD51C, RAD51D, BRIP1, and PALB2, as well as mismatch repair (MMR) genes associated with Lynch syndrome (LS), including MLH1, MSH2, PMS2, and EPCAM.

While the general population has an estimated lifetime ovarian cancer risk of 1.6%, women with BRCA1 gPVs face a 40% to 60% risk, followed by 10% to 20% for those with BRCA2 gPVs, and 3% to 18% for individuals with LS. Despite current guidelines recommending universal germline testing for all patients diagnosed with epithelial ovarian cancer, disparities in referral and uptake persist across racial, ethnic, and geographic groups.

Much prior research has focused on Ashkenazi Jewish women, who have a high prevalence of BRCA1/2 founder mutations, leaving gaps in understanding hereditary ovarian cancer in more diverse populations. Emerging evidence suggests, however, that gPV prevalence in patients from diverse racial and ethnic backgrounds may be comparable to rates observed in Ashkenazi Jewish or non-Hispanic White populations.

To address these gaps, the researchers characterized the germline landscape of patients with ovarian cancer based on self-identified ancestry, using the Myriad Collaborative Research Registry (MCRR), which includes curated, deidentified data from more than 1.2 million patients, including germline, tumor, and gene expression test results.²

Germline Variants Found Beyond Traditionally Recognized High-Risk Populations

The study included patients from the MCRR with ovarian cancer who underwent germline testing between 2010 and 2024. The researchers calculated gPV rates overall and by self-reported ancestry, focusing on HR-related and LS-associated genes.¹

The MCRR included 84,396 patients with ovarian cancer who underwent germline testing. Of these patients, 66.3% (n = 55,984) self-identified as White, 7.2% (n = 6099) as Hispanic, 5.3% (n = 4440) as Black, 4.3% (n = 3628) as Ashkenazi Jewish, 3.4% (n = 2900) as Asian, and 23.3% as other or multiple groups. Additionally, the median age at diagnosis was 56 years. Geographically, the highest representation was from Texas (13%) and California (12%).

Of the study population, 16.1% (n = 13,554) had a deleterious or likely deleterious gPV. A total of 13,750 gPVs were identified, with 234 patients (0.3%) carrying more than 1. Prevalence by ancestry was highest among Ashkenazi Jewish patients (24.4%), followed by Hispanic (18.8%), Asian (17.4%), White (15.6%), and other (14.9%) groups.

HR-related genes were altered in 11,661 patients (13.8%). BRCA1 was the most frequently altered gene (7.6%; n = 6450), followed by BRCA2 (4.9%; n = 4134), ATM (0.3%; n = 278), BRIP1 (0.4%; n = 313), RAD51C (0.3%; n = 223), PALB2 (0.2%; n = 135), and RAD51D (0.2%; n = 128). The researchers observed that HR-related gPV rates varied by ancestry (P < .0001), with the highest overall rate among Ashkenazi Jewish patients (23.7%), followed by Hispanic (16.8%), Asian (15.6%), Black (14.9%), and White (13.1%) individuals.

For LS-associated MMR genes, 778 (0.92%) carried gPVs, most frequently MSH2 (0.32%; n = 272), MSH6 (0.31%; n = 257), PMS2 (0.18%; n = 152), MLH1 (0.11%; n = 93), and EPCAM (0.005%; n = 4). LS-related gPV prevalence was highest in Asian patients (1.3%), followed by White (1.0%), Black (0.74%), Ashkenazi Jewish (0.69%), and Hispanic (0.57%) individuals.

Implications for Equitable Outreach, Genetic Testing

The authors acknowledged several limitations, including reliance on self-reported ancestry. They also excluded patients from 11 states due to privacy laws, which may have introduced bias and limited representation of some minority groups. Still, the researchers noted that their findings highlight the clinical significance of broader outreach and testing.

“…the elevated prevalence observed in populations not traditionally considered at increased risk in our cohort, such as Asian patients, emphasizes that outreach and educational efforts should extend beyond Ashkenazi Jewish communities to ensure equitable access to awareness, genetic testing, and personalized risk assessment for all ancestry groups,” the authors wrote.

References

1. Aryasomayajula C, Johnson CR, Francoeur AA, et al. Pathogenic germline variants among patients with ovarian cancer by self-reported ancestry: a commercial laboratory collaborative research registry study. Gynecol Oncol. Published online November 12, 2025. doi:10.1016/j.ygyno.2025.11.003
2. Myriad Collaborative Research Registry. Myriad Genetics. Accessed December 4, 2025. https://myriad.com/mcrr-researcher/