Multigene testing of moderate-risk genes: be mindful of the missense

Journal of Medical Genetics
E L YoungSean V Tavtigian

Abstract

Moderate-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. We 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. Analysis 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. Among early-onset breast cancer cases, 9.6...Continue Reading

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Citations

Apr 6, 2016·Cancer Letters·Ivana Maleva KostovskaThilo Dörk
Apr 18, 2018·Journal of Medical Genetics·Amy TaylorUNKNOWN UK Cancer Genetics Group (UK-CGG)
May 30, 2020·Radiographics : a Review Publication of the Radiological Society of North America, Inc·Puja P BharuchaNikki P Tirada
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Jul 11, 2018·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Laurent CastéraDominique Vaur
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Mar 5, 2020·Journal of Experimental & Clinical Cancer Research : CR·Giulia Federici, Silvia Soddu
Aug 24, 2021·Current Treatment Options in Oncology·Anusha Vaidyanathan, Virginia Kaklamani

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Methods Mentioned

BETA
genotyping

Software Mentioned

Stata
PolyPhen
rMS
pMSA
Geneious
PHYLIP
CADD
Coffee
MAPP
GVGD

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