Abstract 2056: The genomic landscape of carriers of rare variants in FANCI, a new candidate ovarian cancer predisposing gene
Bibliographic record
Abstract
Abstract The potentially pathogenic variant (PPV), FANCI c.1813C>T; p.L605F, in a new candidate ovarian cancer (OC) predisposing gene was discovered by whole exome sequencing (WES) of familial OC cases from the founder French Canadian (FC) population for discovering new OC predisposing genes. Modeling this variant in cellulo suggested this variant encodes an unstable protein. FANCI is an essential member upstream of the homologous recombination DNA repair pathway and intersects BRCA1 and BRCA2 function, proteins encoded by genes involved in hereditary OC. Investigating the FC founder population facilitates the discovery of PPVs as they are more likely to harbor recurrent variants due to common ancestors, increasing the likelihood of identifying candidate genes in cancer families. To further support the candidacy of FANCI as a new OC predisposing gene, we investigated the germline landscape of c.1813C>T carrier FC OC cases for co-occurring PPVs in known or proposed new (emerging) OC predisposing genes or other genes involved in similar pathways (DNA repair). Using WES of peripheral blood lymphocyte DNA, the genomic landscape of 10 FANCI carriers were investigated for heterozygous PPVs in 276 DNA repair pathways genes, which included known (BRCA1, BRCA2, MSH2, MLH1, MSH6, PMS2) and emerging (BRIP1, RAD51C, RAD51D) OC predisposing genes. Top ranking candidate variants (minor allele frequency <1%) were identified using 11 different in silico tools that assessed amino acid conversation or potential pathogenicity. Pathogenicity of known and emerging OC predisposing genes was assessed using BRCAExchange (www.brcaexchange.org) and ClinVar (www.ncbi.nlm.nih.gov/clinvar/). A similar analysis was done with WES data from 13 FC OC cases harboring pathogenic BRCA1/BRCA2 variants. We identified 31 variants in 27 genes in FANCI c.1813C>T carriers. A previously known carrier of a pathogenic BRCA1 variant (c.2836_2837del; p.Ile946GlnfsTer5) was also identified in a familial case. No carriers of other pathogenic variants in known or emerging OC predisposing genes were found. However, FANCI carriers were found to carry at least one other PPV in a DNA repair pathway gene (range 2-9; average=4.1). There were no other carriers of variants in common among all OC cases, though at least 2 cases carried a variant in the same gene. FC OC cases harboring BRCA1/BRCA2 variants carried at least one other PPV in a DNA repair pathway gene (range 2-7; average 4). It is possible that the identified variants influence or modify risk in conjunction with FANCI, though no PPV was identified in all carriers. As new cancer predisposing genes are identified it will become increasingly important to characterize the genetic context in which variants are identified. This will allow for further insight to clinical translatability once penetrance has been established. Citation Format: Caitlin Fierheller, Wejdan M Alenezi, Corinne Serruya, Timothée Revil, Javad Nadaf, Anne-Marie Mes-Masson, Diane Provencher, William D Foulkes, Zaki El Haffaf, Celia M T Greenwood, Jean-Yves Masson, Jiannis Ragoussis, Patricia N Tonin. The genomic landscape of carriers of rare variants in FANCI, a new candidate ovarian cancer predisposing gene [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2056.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.004 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".