Ovarian cancer

Actionability Pediatric Summary Report

Genes: RAD51C (HGNC:9820) RAD51D (HGNC:9823) BRIP1 (HGNC:20473)
Mode(s) of Inheritance:
Literature Search: 03/17/2017
Curation Status: In Preparation
Release History
Related Reports
Adult Summary Report: (1.1.1)

Secondary Findings in Pediatric Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

Actionability Assertions

Gene Condition (MONDO ID) OMIM ID Final Assertion
RAD51C familial ovarian cancer (0016248) 613399 Assertion Pending
RAD51D familial ovarian cancer (0016248) 614291 Assertion Pending
BRIP1 familial ovarian cancer (0016248) 114480 Assertion Pending

Actionability Assertion 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.

Actionability Scores

Outcome / Intervention Pair Severity Likelihood Effectiveness Nature of Intervention Total Score
No scores were found.

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.
View Citations

Sopik V, et al. (2015) PMID: 25470109, Norquist BM, et al. (2016) PMID: 26720728

Clinical Features (Signs / symptoms)

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.
View Citations

Online Medelian Inheritance in Man. (2012) OMIM: 613399, Daly MB, et al. (2017) PMID: 28040716, Online Medelian Inheritance in Man. (2011) OMIM: 614291

Natural History (Important subgroups & survival / recovery)

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.
View Citations

Norquist BM, et al. (2016) PMID: 26720728, Online Medelian Inheritance in Man. (2012) OMIM: 613399

Description of sources of evidence:

Tier 1: Evidence from a systematic review or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.

Mode of Inheritance

Prevalence of Genetic Variants

Unknown
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 (Includes any high-risk racial or ethnic subgroups)

1-4 %
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 View Citations

Daly MB, et al. (2017) PMID: 28040716

1-4 %
For RAD51D, carriers approach a cumulative risk of 2.6% around age 50 to 54.
Tier 3 View Citations

Daly MB, et al. (2017) PMID: 28040716

5-39 %
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 View Citations

Daly MB, et al. (2017) PMID: 28040716

Relative Risk (Includes any high-risk racial or ethnic subgroups)

>3
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 View Citations

Online Medelian Inheritance in Man. (2012) OMIM: 613399, Daly MB, et al. (2017) PMID: 28040716, Online Medelian Inheritance in Man. (2011) OMIM: 614291, Online Medelian Inheritance in Man. (2013) OMIM: 602774

Expressivity

There may be the presence of additive risk factors that may increase the risk of early onset ovarian cancer.
Tier 4 View Citations

Daly MB, et al. (2017) PMID: 28040716

Description of sources of evidence:

Tier 1: Evidence from a systematic review or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.

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 View Citations

Daly MB, et al. (2017) PMID: 28040716, Scottish Intercollegiate Guidelines Network (SIGN). (2013) URL: www.sign.ac.uk.

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 View Citations

Moyer VA, et al. (2014) PMID: 24366376, Nelson, H.D., Fu, R., Goddard, K., Mitchell, J.P., Okinaka-Hu, L., Pappas, M., Zakher, B.. (2013) URL: www.ncbi.nlm.nih.gov.

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 View Citations

Scottish Intercollegiate Guidelines Network (SIGN). (2013) URL: www.sign.ac.uk.

A similar recommendation was not identified for BRIP1.

Description of sources of evidence:

Tier 1: Evidence from a systematic review or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.

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.
Context: Adult
View Citations

Daly MB, et al. (2017) PMID: 28040716, Moyer VA, et al. (2014) PMID: 24366376

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.
Context: Adult
Tier 1 View Citations

Moyer VA, et al. (2014) PMID: 24366376, Nelson, H.D., Fu, R., Goddard, K., Mitchell, J.P., Okinaka-Hu, L., Pappas, M., Zakher, B.. (2013) URL: www.ncbi.nlm.nih.gov.

Description of sources of evidence:

Tier 1: Evidence from a systematic review or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Gene Condition Associations
OMIM Identifier Primary MONDO Identifier Additional MONDO Identifiers
RAD51C 613399 0016248 0013253
RAD51D 614291 0016248 0013669
BRIP1 114480 0016248

References List

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

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

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. (2017) NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast and Ovarian, Version 2.2017. Journal of the National Comprehensive Cancer Network : JNCCN. 15(1):9-20.

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

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) URL: https://www.ncbi.nlm.nih.gov/books/NBK179201/

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. (2016) Inherited Mutations in Women With Ovarian Carcinoma. JAMA oncology. 2(4):482-90.

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

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

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

Early Rule-Out Summary

This topic did not pass the early rule out stage due to insufficient evidence for actionability. Thus, this topic did not move forward for a full evidence curation and summary report. This topic may be reconsidered if additional evidence becomes available.

Findings of Early Rule-Out Assessment

  1. Is there a qualifying resource, such as a practice guideline or systematic review, for the genetic condition?
  2. Does the practice guideline or systematic review indicate that the result is actionable in one or more of the following ways?

    3. a. Patient Management

    b. Surveillance or Screening

    c. Circumstances to Avoid

  3. Is there an intervention that is initiated during childhood (<18 years of age) in an undiagnosed child with the genetic condition?
  4. Does the disease present outside of the neonatal period?
  5. Is this condition an important health problem?
  6. Is there at least on known pathogenic variant with at least moderate penetrance (≥40%) or moderate relative risk (≥2) in any population?