ArticleJournal of medical genetics2016
Multigene testing of moderate-risk genes: be mindful of the missense.
Article in Journal of medical genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers, 1 of them a synthesis that pooled it.
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Who cites it
21 citing papers in PubMed, 1 synthesis or guideline pooled it.
- ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Pooled it
- When two plus four does not equal six: Combining computational and functional evidence to classify BRCA1 key domain missense substitutions.American journal of human genetics · 2025Article
- Identification and characterization of ATM founder mutation in BRCA-negative breast cancer patients of Arab ethnicity.Scientific reports · 2023Article
- What Is Known about Breast Cancer in Young Women?Cancers · 2023Review
- Article
- Understanding the Clinical Implications of Low Penetrant Genes and Breast Cancer Risk.Current treatment options in oncology · 2021Review
- Population-Based Estimates of the Age-Specific Cumulative Risk of Breast Cancer for Pathogenic Variants inCancers · 2021Article
- Review
- Literature Review ofGenes · 2020Review
- Variants of uncertain significance in the era of high-throughput genome sequencing: a lesson from breast and ovary cancers.Journal of experimental & clinical cancer research : CR · 2020Review
- Results of multigene panel testing in familial cancer cases without genetic cause demonstrated by single gene testing.Scientific reports · 2019Article
- Assessing the performance of in silico methods for predicting the pathogenicity of variants in the gene CHEK2, among Hispanic females with breast cancer.Human mutation · 2019Article
- Landscape of pathogenic variations in a panel of 34 genes and cancer risk estimation from 5131 HBOC families.Genetics in medicine : official journal of the American College of Medical Genetics · 2018Article
- Article
- Consensus for genes to be included on cancer panel tests offered by UK genetics services: guidelines of the UK Cancer Genetics Group.Journal of medical genetics · 2018Article
- Combined annotation-dependent depletion score for BRCA1/2 variants in patients with breast and/or ovarian cancer.Cancer science · 2018Article
- Variants of cancer susceptibility genes in Korean BRCA1/2 mutation-negative patients with high risk for hereditary breast cancer.BMC cancer · 2018Article
- Rare, protein-truncating variants inJournal of medical genetics · 2017Article
- Article
- Endometrial cancer gene panels: clinical diagnostic vs research germline DNA testing.Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc · 2017Review
Corrections and comments
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Authors and funding
30 authors.
Funding
Abstract
backgroundModerate-risk genes have not been extensively studied, and missense substitutions in them are generally returned to patients as variants of uncertain significance lacking clearly defined risk estimates. The fraction of early-onset breast cancer cases carrying moderate-risk genotypes and quantitative methods for flagging variants for further analysis have not been established.
methodsWe evaluated rare missense substitutions identified from a mutation screen of ATM, CHEK2, MRE11A, RAD50, NBN, RAD51, RINT1, XRCC2 and BARD1 in 1297 cases of early-onset breast cancer and 1121 controls via scores from Align-Grantham Variation Grantham Deviation (GVGD), combined annotation dependent depletion (CADD), multivariate analysis of protein polymorphism (MAPP) and PolyPhen-2. We also evaluated subjects by polygenotype from 18 breast cancer risk SNPs. From these analyses, we estimated the fraction of cases and controls that reach a breast cancer OR≥2.5 threshold.
resultsAnalysis of mutation screening data from the nine genes revealed that 7.5% of cases and 2.4% of controls were carriers of at least one rare variant with an average OR≥2.5. 2.1% of cases and 1.2% of controls had a polygenotype with an average OR≥2.5.
conclusionsAmong early-onset breast cancer cases, 9.6% had a genotype associated with an increased risk sufficient to affect clinical management recommendations. Over two-thirds of variants conferring this level of risk were rare missense substitutions in moderate-risk genes. Placement in the estimated OR≥2.5 group by at least two of these missense analysis programs should be used to prioritise variants for further study. Panel testing often creates more heat than light; quantitative approaches to variant prioritisation and classification may facilitate more efficient clinical classification of variants.
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