Incidence of germline mutations in risk genes including BRCA1/2 in consecutive ovarian cancer (OC) patients (AGO TR-1)

Abstract
 
Background: Identification of families at risk for OC including recommendation for prophylactic surgery is the only effective method to reduce OC mortality. In addition, BRCA1/2 mutations are known as prognostic factor and target for treatment.

Methods: Prospective counseling and testing of consecutive patients with first diagnosis or platinum sensitive relapse of invasive epithelial OC. Testing of 25 risk genes related to ovarian cancer. A positive mutation was defined as class 4/5 mutation and a positive family history was defined as at least one relative with breast cancer (BC) or OC or BC in personal history.

Results: In total, 529 pts entered the study, of which 507 were analyzed so far: 270 (53%) patients with first diagnosis of OC and 237 (47%) patients with platinum sensitive relapse. In total, 21% were BRCA1/2 positive (BRCA positive) and 27% for a mutation in at least one risk gene. The incidence of mutations in BRCA1 was 15%, BRCA2: 6%, RAD51C: 1.8%, PALB2: 1.2%. Mutations in all others were found less frequently (< 1%). In elderly patients (> 70 years), 13% carried a mutation in a risk gene compared to 31% of patients ≤70 years (p < 0.001). Family history identified 69% of the BRCA1/2 positive patients, but missed 31%.

Conclusions: 27% of all OC pts harbor a positive mutation in the genes analyzed. Age and FH are insufficient for identifying these patients. Genetic testing should therefore be offered to every patient with invasive epithelial ovarian cancer; limiting testing to BRCA1/2 analysis seems insufficient.
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Invitae approaches variant classification from a strict Mendelian perspective and employs the recommended five-tier classification system recommended by ACMG. A sequence change can be classified as:

• (5) Pathogenic — This variant directly contributes to the development of disease. Some pathogenic variants may not be fully penetrant. In the case of recessive or X-linked conditions, a single pathogenic variant may not be sufficient to cause disease on its own. Additional evidence is not expected to alter the classification of this variant.

• (4) Likely pathogenic — This variant is very likely to contribute to the development of disease however, the scientific evidence is currently insufficient to prove this conclusively. Additional evidence is expected to confirm this assertion of pathogenicity, but we cannot fully rule out the possibility that new evidence may demonstrate that this variant has little or no clinical significance.
• Uncertain significance — There is not enough information at this time to support a more definitive classification of this variant.
• Likely benign — This variant is not expected to have a major effect on disease however, the scientific evidence is currently insufficient to prove this conclusively. Additional evidence is expected to confirm this assertion, but we cannot fully rule out the possibility that new evidence may demonstrate that this variant can contribute to disease.
• Benign — This variant does not cause disease.

One additional classification is also periodically invoked to capture variable expressivity:

• Pathogenic (low penetrance) — This variant is commonly accepted as a contributing factor of disease, but the penetrance of this particular change is sufficiently low (<25%) to be often seen in individuals without disease. As a result, the predictive value of this information is considered to be low.