Hereditary Ovarian Cancer Panel

Ovarian cancer accounts for approximately 3.7% of all cancer in women and accounts for 4.2% of all deaths in women annually (Toss et al. 2015. PubMed ID: 26075229). Twenty-three percent of cases have a hereditary component, and 65%-85% of these cases are attributed to variants in BRCA1 and BRCA2 (Toss et al. 2015. PubMed ID: 26075229; Nakonechny and Gilks. 2016. PubMed ID: 27241103). The remaining hereditary cases are attributed to variants within genes that encode additional components of the mismatch repair machinery, double-strand break repair, and tumor suppressor genes important for regulation and activation of cell proliferation, apoptosis, and genomic stability (Toss et al. 2015. PubMed ID: 26075229; Nakonechny and Gilks. 2016. PubMed ID: 27241103).

More than 90% of ovarian cancers are derived from epithelial cells, while 10% develop from germ cells or granulosa-theca cells (Toss et al. 2015. PubMed ID: 26075229). Ovarian cancers can be classified into five histotypes: high-grade serous carcinoma (HGSC), low-grade serous carcinoma (LGSC), clear cell carcinoma (CCC), endometrioid carcinoma (EC), and mucinous carcinoma (MC; Nakonechny and Gilks. 2016. PubMed ID: 27241103). HGSC is the most common ovarian cancer histotype (68% of cases) and is predominantly derived from cells of the ovarian epithelium or fallopian tubes, specifically the fimbriated or distal portion (Singh et al. 2015. PubMed ID: 26126051). CCC is the second most common histotype of ovarian carcinoma in western populations (~12%; Köbel et al. 2010. PubMed ID: 20407318) and has a higher incidence in individuals of Japanese descent (Nakonechny and Gilks. 2016. PubMed ID: 27241103). EC is the third most common type, and approximately 20% of individuals present with endometriosis in either the ovary or elsewhere in the pelvic region. LGSC and MC collectively account for 6-7% of ovarian carcinomas, with the mean age of MC presentation around 45 years (Nakonechny and Gilks. 2016. PubMed ID: 27241103).

Most cases of hereditary ovarian cancer are associated with a concurrent diagnosis of hereditary breast and ovarian cancer (known as HBOC) or Lynch syndrome (LS). HBOC is an inherited disorder that is highly associated with tumors of the breasts and ovaries. HBOC cases tend to arise prior to age 50, with tumors often occurring bilaterally. Multiple family members are often affected (including males with breast cancer). Patients with HBOC have a 45%-50% increased lifetime risk of developing the HGSC ovarian carcinoma histotype, while individuals with Lynch syndrome have an ~10% increased lifetime risk of developing the EC or CCC ovarian carcinoma histotypes (Risch et al. 2001. PubMed ID: 11179017; McAlpine et al. 2012. PubMed ID: 22282309). Conversely, 15%-25% of women with a diagnosis of HGSC will also have HBOC; therefore, HBOC testing is strongly suggested for these individuals (Nakonechny and Gilks. 2016. PubMed ID: 27241103).

Hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS) are the two most common autosomal dominant cancer susceptibility syndromes that include individuals who present with ovarian cancers. Double-strand break repair via homologous recombination (HR) or non-homologous end joining (NHEJ) is associated with HBOC. HR components are encoded by numerous genes, including BRCA1, BRCA2, ATM, CHEK2, RAD51, BRIP1, and PALB2. Collectively, the products of these genes respond to double-strand breaks through kinase activity, which leads to cell cycle arrest in either G1-S, S, or G2-M phase via BRCA1-dependent mechanisms. Double-strand DNA breaks are then repaired through a mechanism that utilizes the sister chromatid as a template (Seal et al. 2006. PubMed ID: 17033622; Rahman et al. 2007. PubMed ID: 17200668; Toss et al. 2015. PubMed ID: 26075229). In the absence of a functioning HR pathway, double-strand breaks must be repaired via non-homologous end joining (NHEJ), which does not utilize a sister chromatid as a template and is error prone, subsequently increasing the risk of novel defects and cancer (Lieber et al. 2010. PubMed ID: 20012587). Variants in BRCA1/BRCA2 account for 65%-85% of hereditary ovarian cancers, with the majority of variants being missense, nonsense, or small frameshift deletions (Human Gene Mutation Database; Toss et al. 2015. PubMed ID: 26075229; Nakonechny and Gilks. 2016. PubMed ID: 27241103).

Lynch syndrome (LS) is an autosomal dominant cancer susceptibility disease that results from variants within genes that are associated with the mismatch repair (MMR) system. Single-strand breaks are repaired via base excision repair or nucleotide excision repair systems which include components encoded by MLH1, MSH2, MSH6, and PMS2. Approximately 90% of germline variants are located in MLH1 and MLH2 and approximately 10% in MSH6 and PMS2. Germline deletions in EPCAM, which is not a mismatch repair gene, inactivates MSH2 in about 1% of individuals diagnosed with Lynch syndrome (Jang et al. 2010. PubMed ID: 20559516; Bonadona et al. 2015. PubMed ID: 21642682; Kohlman and Gruber. 2018. PubMed ID: 20301390). LS-associated ovarian cancers tend to occur at an early age, are low-grade, and are usually detected early in tumor progression (Niskakoski et al. 2013. PubMed ID: 23716351).

Hereditary breast and/or ovarian cancers can sometimes be associated with other hereditary cancer syndromes including Cowden, Li-Fraumeni, Peutz-Jeghers, hereditary diffuse gastric cancer, and Lynch syndrome (Berlinear et al. 2013. PubMed ID: 23188549). Variants in TP53 have been implicated as the cause of Li-Fraumeni syndrome. Breast cancer appears as a feature of this syndrome, and carriers of TP53 variants are at high risk of developing early onset breast and ovarian cancer (Antoniou et al. 2006. PubMed ID: 16998504; Kraus et al. 2017. PubMed ID: 27616075). Individuals with Cowden syndrome caused by mutations in PTEN have a lifetime risk of 50% for breast cancer and 5-10% for endometrial cancer (Apostolou et al. 2013. PubMed ID: 23586058). Peutz-Jeghers syndrome, caused by pathogenic variants in STK11, can reach a breast cancer incidence of 32% by 60 years of age (Lim et al. 2004. PubMed ID: 15188174; Hearle et al. 2006. PubMed ID: 16707622).

Other genes that are thought to confer low to moderate risk of breast and ovarian cancer have been identified:

Pathogenic variants in CDH1 have been shown to be associated with the development of invasive lobular carcinoma. It is also thought to be a gene that causes an intermediate risk of hereditary breast and ovarian cancer (Masciari et al. 2007. PubMed ID: 17660459; Kraus et al. 2017. PubMed ID: 27616075).

CHEK2 truncating variants have been shown to confer a moderate risk of breast and ovarian cancer development (Meijers-Heijboer et al. 2002. PubMed ID: 11967536; Tan et al. 2008. PubMed ID: 18682420; Walsh et al. 2011. PubMed ID: 22006311).

ATM is a known ovarian cancer predisposition gene. Additionally, variants in ATM that cause ataxia telangiectasia in biallelic carriers confer a twofold increased risk of breast cancer development in monoallelic carriers (Tan et al. 2008. PubMed ID: 18682420).

Pathogenic variants in BRIP1 result in ~0.4% increased risk of ovarian cancer in Icelandic populations (Ramus et al. 2015. PubMed ID: 26315354). Ovarian tumors from carriers of BRIP1 variants show loss of the wild type allele, suggesting its tumor suppressor capabilities. Frameshift variants in BRIP1 also show an increased risk of invasive ovarian cancer (Rafnar et al. 2011. PubMed ID: 21964575).

PALB2 is also considered a gene with moderate risk alleles and causes a 2- to 4-fold increased risk of breast cancer (Caminsky et al. 2016. PubMed ID: 26898890). It is considered an ovarian cancer susceptibility gene (Ramus et al. 2015. PubMed ID: 26315354).

RAD51C, essential for homologous recombination repair, has been reported to be a hereditary breast and ovarian cancer susceptibility gene; several pathogenic variants have been identified in BRCA1/2-negative HBOC families (Clague et al. 2011. PubMed ID: 21980511). RAD51C is mutated in approximately 1-5% of individuals with a family history of breast and ovarian cancer (Meindl et al. 2011. PubMed ID: 21637635).

The relative risk of ovarian and breast cancer for RAD51D variant carriers was estimated to be 6.3 and 1.3, respectively (Loveday et al. 2011. PubMed ID: 21822267).

Large multi-exon deletions and insertions in BARD1 may substantially contribute to familial breast and ovarian cancer risk (Klonowska et al. 2015. PubMed ID: 25994375).

Pathogenic NBN variants have been identified in individuals with ovarian cancer and are associated with a twofold increased risk of breast cancer (Walsh et al. 2011. PubMed ID: 22006311).

Pathogenic variants in the MUTYH gene have been associated with hereditary breast and ovarian cancer (Maxwell et al. 2014. PubMed ID: 25503501; Schrader et al. 2016. PubMed ID: 26556299).

Other genes thought to confer an increased risk of HBOC and Lynch syndrome include CHEK1 (Dutil et al. 2019. PubMed ID: 31780696), DICER1 (Jalkh et al. 2017. PubMed ID: 28202063), FANCA (Litim et al. 2013. PubMed ID: 23021409; Jalkh et al. 2017. PubMed ID: 28202063), FANCM (Figlioli et al. 2020. PubMed ID: 31991861), MRE11 (Heikkinen et al. 2003. PubMed ID: 14684699), RAD1(Lopes et al. 2019. PubMed ID: 31078449), RAD50 (van der Merwe et al. 2017. PubMed ID: 28241424; Sung et al. 2017. PubMed ID: 28961279), SMARCA4 (Witkowski et al. 2014. PubMed ID: 24658002; Hayano et al. 2016. PubMed ID: 27701467), and TP53I3 (Lopes et al. 2019. PubMed ID: 31078449).

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.

Less than 1% of the general population has a pathogenic variant in the BRCA1 or BRCA2 genes according to current estimates, and 10-15% of women diagnosed with breast cancer have a pathogenic variant in one of these genes with an increased incidence of monoallelic carriers having ovarian cancer (Turnbull et al. 2008. PubMed ID: 18544032; Tan et al. 2008. PubMed ID: 18682420). In the German population, CHEK2 pathogenic variants are found in around 4% of all cases of hereditary breast cancer. The prevalence of PALB2 pathogenic variants in the populations of both Germany and England is approximately 1% (Meindl et al. 2011. PubMed ID: 21637635). Approximately 6% of patients with hereditary ovarian cancers who do not have pathogenic variants in BRCA1 or BRCA2 have pathogenic variants in BARD1, BRIP1, CHEK2, MRE11A, NBN, PALB2, RAD50, RAD51C, RAD51D, and TP53 (Walsh et al. 2011. PubMed ID: 22006311; Loveday et al. 2011. PubMed ID: 21822267). Highly penetrant variants in other genes such as STK11, CDH1, and PTEN account for less than 1% of ovarian cancer cases (Minion et al. 2015. PubMed ID: 25622547). Pathogenic sequence variants in the MLH1, MSH2, MSH6, and PMS2 genes account for approximately 50%, 40%, 7-10%, and <5% of Lynch syndrome cases, respectively (Kohlmann and Gruber. 2018. PubMed ID: 20301390).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.8% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. 

Deletion and duplication testing for STK11, NF1, and PMS2 is performed using NGS, but CNVs detected in these genes are usually confirmed via multiplex ligation-dependent probe amplification (MLPA).

DNA analysis of the PMS2 gene is complicated due to the presence of several pseudogenes. One particular pseudogene, PMS2CL, has high sequence similarity to PMS2 exons 11 to 15 (Blount et al. 2018. PubMed ID: 29286535). Next-generation sequencing (NGS) based copy number variant (CNV) analysis can detect deletions and duplications involving exons 1 to 10 of PMS2 but has less sensitivity for exons 11 through 15. Multiplex ligation-dependent probe amplification (MLPA) can detect deletions and duplications involving PMS2 exons 1 to 15. Of note, PMS2 MLPA is included in this test.