Published 2018
| Version v1
Publication
Prevalence of pathogenic/likely pathogenic variants in the 24 cancer genes of the ACMG Secondary Findings v2.0 list in a large cancer cohort and ethnicity-matched controls
Creators
- Kim, Jung
- Luo, Wen
- Wang, Mingyi
- Wegman-Ostrosky, Talia
- Frone, Megan N
- Johnston, Jennifer J
- Nickerson, Michael L
- Rotunno, Melissa
- Li, Shengchao A
- Achatz, Maria I
- Brodie, Seth A
- Dean, Michael
- de Andrade, Kelvin C
- Fortes, Fernanda P
- Gianferante, Matthew
- Khincha, Payal
- McMaster, Mary L
- McReynolds, Lisa J
- Pemov, Alexander
- Pinheiro, Maisa
- Santiago, Karina M
- Alter, Blanche P
- Caporaso, Neil E
- Gadalla, Shahinaz M
- Goldin, Lynn R
- Greene, Mark H
- Loud, Jennifer
- Yang, Xiaohong R
- Freedman, Neal D
- Gapstur, Susan M
- Gaudet, Mia M
- Calista, Donato
- Ghiorzo, Paola
- Fargnoli, Maria Concetta
- Nagore, Eduardo
- Peris, Ketty
- Puig, Susana
- Landi, Maria Teresa
- Hicks, Belynda
- Zhu, Bin
- Liu, Jia
- Sampson, Joshua N
- Chanock, Stephen J
- Mirabello, Lisa J
- Morton, Lindsay M
- Biesecker, Leslie G
- Tucker, Margaret A
- Savage, Sharon A
- Goldstein, Alisa M
- Stewart, Douglas R
Contributors
Others:
- Kim, Jung
- Luo, Wen
- Wang, Mingyi
- Wegman-Ostrosky, Talia
- Frone, Megan N
- Johnston, Jennifer J
- Nickerson, Michael L
- Rotunno, Melissa
- Li, Shengchao A
- Achatz, Maria I
- Brodie, Seth A
- Dean, Michael
- de Andrade, Kelvin C
- Fortes, Fernanda P
- Gianferante, Matthew
- Khincha, Payal
- Mcmaster, Mary L
- Mcreynolds, Lisa J
- Pemov, Alexander
- Pinheiro, Maisa
- Santiago, Karina M
- Alter, Blanche P
- Caporaso, Neil E
- Gadalla, Shahinaz M
- Goldin, Lynn R
- Greene, Mark H
- Loud, Jennifer
- Yang, Xiaohong R
- Freedman, Neal D
- Gapstur, Susan M
- Gaudet, Mia M
- Calista, Donato
- Ghiorzo, Paola
- Fargnoli, Maria Concetta
- Nagore, Eduardo
- Peris, Ketty
- Puig, Susana
- Landi, Maria Teresa
- Hicks, Belynda
- Zhu, Bin
- Liu, Jia
- Sampson, Joshua N
- Chanock, Stephen J
- Mirabello, Lisa J
- Morton, Lindsay M
- Biesecker, Leslie G
- Tucker, Margaret A
- Savage, Sharon A
- Goldstein, Alisa M
- Stewart, Douglas R
Description
Background: Prior research has established that the prevalence of pathogenic/likely pathogenic (P/LP) variants across all of the American College of Medical Genetics (ACMG) Secondary Findings (SF) genes is approximately 0.8-5%. We investigated the prevalence of P/LP variants in the 24 ACMG SF v2.0 cancer genes in a family-based cancer research cohort (n = 1173) and in cancer-free ethnicity-matched controls (n = 982). Methods: We used InterVar to classify variants and subsequently conducted a manual review to further examine variants of unknown significance (VUS). Results: In the 24 genes on the ACMG SF v2.0 list associated with a cancer phenotype, we observed 8 P/LP unique variants (8 individuals; 0.8%) in controls and 11 P/LP unique variants (14 individuals; 1.2%) in cases, a non-significant difference. We reviewed 115 VUS. The median estimated per-variant review time required was 30 min; the first variant within a gene took significantly (p = 0.0009) longer to review (median = 60 min) compared with subsequent variants (median = 30 min). The concordance rate was 83.3% for the variants examined by two reviewers. Conclusion: The 115 VUS required database and literature review, a time- and labor-intensive process hampered by the difficulty in interpreting conflicting P/LP determinations. By rigorously investigating the 24 ACMG SF v2.0 cancer genes, our work establishes a benchmark P/LP variant prevalence rate in a familial cancer cohort and controls.
Additional details
Identifiers
- URL
- http://hdl.handle.net/11567/935478
- URN
- urn:oai:iris.unige.it:11567/935478
Origin repository
- Origin repository
- UNIGE