Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Passed (Consensus scoring is Complete)
• Curation Status (Adult): Released - Under Revision 1.1.1
• Status (Pediatric): Incomplete (Consensus scoring is Incomplete)
• GENE/GENE PANEL: RAD51C, RAD51D, BRIP1
• Condition: Ovarian cancer
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• RAD51C ⇔ 0016248 (breast-ovarian cancer, familial, susceptibility to, 3; brovca3): Assertion Pending
• RAD51D ⇔ 0016248 (breast-ovarian cancer, familial, susceptibility to, 4; brovca4): Assertion Pending
• BRIP1 ⇔ 0016248 (breast cancer): Assertion Pending

Actionability Rationale

This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Final Consensus Scores

Gene Condition Pairs: RAD51C ⇔ 0016248 (OMIM:613399) RAD51D ⇔ 0016248 (OMIM:614291) BRIP1 ⇔ 0016248 (OMIM:114480)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Ovarian cancer / Oophorectomy	2	1C	3B	1	7CB

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

The prevalence of familial breast-ovarian cancer associated with heterozygous germline pathogenic variants in the RAD51C, RAD51D, or BRIP1 genes in the general population is not clear. A recent review estimated that altogether, RAD51C pathogenic variants have been identified in 29 breast or ovarian cancer probands with a family history of ovarian cancer, with an overall prevalence of 0.84%. A study of 1915 women with ovarian cancer with available germline DNA, unselected for age or family history, reported a frequency of 0.6% of RAD51C and RAD51D and 1.4% of BRIP1 pathogenic variants. [1, 2]

Clinical Features

Pathogenic variants in RAD51C , RAD51D, and BRIP1 are associated with an increased risk of ovarian cancer. However, there is currently insufficient evidence for the risk of breast cancer associated with these genes. [3, 4, 5]

Natural History

A study of 6 unrelated German pedigrees indicated that the mean age of onset of ovarian cancer associated with RAD51C was 60 years, 8 years younger than the mean age of onset of ovarian cancer of 68 years in the general population. A US-based study of 1915 women with ovarian cancer with available germline DNA, unselected for age or family history, reported mean ages of onset of 64, 54, and 65.5 for individuals with pathogenic variants in RAD51C, RAD51D, and BRIP1, respectively. Individuals in the same study without an identified mutation had a median age of onset of 62 years. [2, 3]

2. How effective are interventions for preventing harm?

Patient Management

Based on estimates from available studies, the lifetime risk of ovarian cancer in carriers of pathogenic variants in RAD51C, RAD51D , and BRIP1 appears to be sufficient to justify consideration of risk-reducing salpingo-oophorectomy (RRSO). However, the current evidence is insufficient to make a firm recommendation as to the optimal age for RRSO. The argument has been made that RRSO should not be considered until a woman’s expected lifetime risk of developing ovarian cancer exceeds 2.6%, the expected lifetime risk of a woman with a BRCA-negative family history of ovarian cancer. The cumulative risk for developing ovarian cancer does not approach 2.6% until ages 60 to 64 for RAD51C, ages 50 to 54 for RAD51D, and ages 50 to 55 years for BRIP1. However, some women may have additive risk factors and delaying the discussion of RRSO until these age ranges may miss some cases of early-onset ovarian cancer. Therefore, based on the current, limited evidence base, it has been recommended for carriers of RAD51C, RAD51D, and BRIP1 pathogenic variants that a discussion about RRSO should be held around age 45–50 years or earlier based on a specific family history of an earlier onset ovarian cancer. (Tier 2) [4, 6]

Evidence on the effectiveness of reducing risk of ovarian cancer following RRSO in patients with pathogenic variants in RAD51C, RAD51C, and BRIP1 was not available. However, studies in women who are at high risk, including those with BRCA1 an BRCA2 mutations, show a reduction in risk of ovarian cancer by 69-100%. (Tier 1) [7, 8]

Surveillance

Screening for ovarian cancer in high risk groups, including carriers of pathogenic variants in RAD51C and RAD51D, should only be offered in the context of a research study. (Tier 2) [6]

A similar recommendation was not identified for BRIP1.

Circumstances to Avoid

No circumstances-to-avoid recommendations have been provided for the Adult context.

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

The prevalence of pathogenic mutations associated with an increased risk of ovarian cancer in RAD51C, RAD51D, and BRIP1 in the general population is unknown.

Penetrance

The cumulative risk of developing ovarian cancer in carriers of a RAD51C pathogenic variant approaches 2.6% around ages 60 to 64 years, with the cumulative risk between the ages of 55 to 59 being 1.5%. (Tier 3) [4]

For RAD51D, carriers approach a cumulative risk of 2.6% around age 50 to 54. (Tier 3) [4]

The cumulative lifetime risk of developing ovarian cancer by age 80 in carriers of BRIP1 pathogenic variants is estimated to be 5.8%. (Tier 3) [4]

Relative Risk

The relative risk of ovarian cancer for RAD51C and RAD51D has been estimated as 5.88 (95% CI: 2.91–11.88) and 6.30 (95% CI: 2.86–13.85), respectively. However, literature related to risk of ovarian cancer and BRIP1 is odds ratios estimated from case-control studies, which are likely similar to relative risks given the rarity of this outcome in the general population: 8.13 (95% CI: 4.74-13.95) to 11.22 (95% CI: 3.22–34.10). (Tier 3) [3, 4, 5, 9]

Expressivity

There may be the presence of additive risk factors that may increase the risk of early onset ovarian cancer. (Tier 4) [4]

4. What is the Nature of the Intervention?

Nature of Intervention

In women with BRCA1 and/or BRCA2 mutations who underwent an RRSO, 5% of women with a personal history of breast cancer expirenced a surgical complication. In a second study women with BRCA1 and/or BRCA2 mutations who underwent surgery at a mean age of 47 (47% with a personal history of breast cancer), most women reported worsening of vasomotor symptoms, and decreased sexual functioning after surgery. Guidelines state that the decision to carry out RRSO should not be made lightly, given the impact of premature menopause. [4, 7]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

There are currently no ovarian cancer surveillance in the general population. Ovarian cancer is typically metastatic when diagnosed, thus RRSO is the only effective strategy to reduce the risk of dying from ovarian cancer. (Tier 1) [7, 8]

Date of Search: 03.17.2017

Reference List

1. Sopik V, Akbari MR, Narod SA. Genetic testing for RAD51C mutations: in the clinic and community. Clin Genet. (2015) 88(4):303-12.

2. Norquist BM, Harrell MI, Brady MF, Walsh T, Lee MK, Gulsuner S, Bernards SS, Casadei S, Yi Q, Burger RA, Chan JK, Davidson SA, Mannel RS, DiSilvestro PA, Lankes HA, Ramirez NC, King MC, Swisher EM, Birrer MJ. Inherited Mutations in Women With Ovarian Carcinoma. JAMA Oncol. (2016) 2(4):482-90.

3. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 3; BROVCA3. MIM: 613399: 2012 May 16. World Wide Web URL: http://omim.org.

4. Daly MB, Pilarski R, Berry M, Buys SS, Farmer M, Friedman S, Garber JE, Kauff ND, Khan S, Klein C, Kohlmann W, Kurian A, Litton JK, Madlensky L, Merajver SD, Offit K, Pal T, Reiser G, Shannon KM, Swisher E, Vinayak S, Voian NC, Weitzel JN, Wick MJ, Wiesner GL, Dwyer M, Darlow S. NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast and Ovarian, Version 2.2017. J Natl Compr Canc Netw. (2017) 15(1):9-20.

5. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 4; BROVCA4. MIM: 614291: 2011 Oct 17. World Wide Web URL: http://omim.org.

6. Scottish Intercollegiate Guidelines Network (SIGN). Management of epithelial ovarian cancer. A national clinical guideline. SIGN publication no. 135. (2013) Website: http://www.sign.ac.uk/assets/sign135.pdf

7. Moyer VA. Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. (2014) 160(4):271-81.

8. Nelson, H.D., Fu, R., Goddard, K., Mitchell, J.P., Okinaka-Hu, L., Pappas, M., Zakher, B. Risk Assessment, Genetic Couseling, And Genetic Testing for BRCA-Related Cancer: Systematic Review to Update the U.S. Preventive Servicies Task Force Recommendation. Evidence Synthesis Number 101. Report No.: AHRQ Publication No. 12-05164-EF-1. (2013) Website: https://www.ncbi.nlm.nih.gov/books/NBK179201/

9. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. RAD51, S. CEREVISIAE, HOMOLOG OF, C; RAD51C. MIM: 602774: 2013 Dec 04. World Wide Web URL: http://omim.org.