Human Mutation

Cover image for Vol. 38 Issue 2

Edited By: Garry R. Cutting

Impact Factor: 5.089

ISI Journal Citation Reports © Ranking: 2015: 23/166 (Genetics & Heredity)

Online ISSN: 1098-1004

Virtual Issue: Evaluating Mutation Pathogenicity

Edited by Sean V. Tavtigian and Marc S. Greenblatt

UPDATED May 2013: Advances in genetic medicine offer the promise of more effective healthcare. Clinicians often make decisions regarding management of cancer or inherited disease based on whether a patient carries a presumed causative variant. Goldgar et al. (Am J Hum Genet 75:535, 2004) set standards by which BRCA1/2 variants could be classified as pathogenic. In addition to refining classification standards for these and other cancer and disease genes, improved methods for evaluating variant pathogenicity and collating/distributing these data are crucial. Presented here are Human Mutation articles from 2007-2012 illustrating the progress, pitfalls, and prospects of classifying and evaluating variants for cancer susceptibility and other inherited disorders.

New articles have been added to the top. The editors regret limitations in space that preclude inclusion of all relevant articles.

See also the 2008 Special Issue: Assessing Mutation Pathogenicity in Cancer Susceptibility Genes


Guidelines for splicing analysis in molecular diagnosis derived from a set of 327 combined in silico/in vitro studies on BRCA1 and BRCA2 variants
Claude Houdayer, Virginie Caux-Moncoutier, Sophie Krieger, Michel Barrois, Françoise Bonnet, Violaine Bourdon, Myriam Bronner, Monique Buisson, Florence Coulet, Pascaline Gaildrat, Cédrick Lefol, Mélanie Léone, Sylvie Mazoyer, Danielle Muller, Audrey Remenieras, Françoise Révillion, Etienne Rouleau, Joanna Sokolowska, Jean-Philippe Vert, Rosette Lidereau, Florent Soubrier, Hagay Sobol, Nicolas Sevenet, Brigitte Bressac-de Paillerets, Agnès Hardouin, Mario Tosi, Olga M. Sinilnikova and Dominique Stoppa-Lyonnet

A Classification Model Relative to Splicing for Variants of Unknown Clinical Significance: Application to the CFTR Gene
Caroline Raynal, David Baux, Corinne Theze, Corinne Bareil, Magali Taulan, Anne-Françoise Roux, Mireille Claustres, Sylvie Tuffery-Giraud and Marie des Georges

Analysis of BRCA1 Variants in Double-Strand Break Repair by Homologous Recombination and Single-Strand Annealing
William I. Towler, Jie Zhang, Derek J. R. Ransburgh, Amanda E. Toland, Chikashi Ishioka, Natsuko Chiba and Jeffrey D. Parvin


Guidelines for Reporting and Using Prediction Tools for Genetic Variation Analysis
Mauno Vihinen

Pathological assessment of mismatch repair gene variants in lynch syndrome: past, present and future
Lene Juel Rasmussen, Christopher D. Heinen, Brigitte Royer-Pokora, Mark Drost, Sean Tavtigian, Robert M.W. Hofstra and Niels de Wind

Assessment of the potential pathogenicity of missense mutations identified in the GTPase-activating protein (GAP)-related domain of the neurofibromatosis type-1 (NF1) gene
Laura Thomas, Mark Richards, Matthew Mort, Elaine Dunlop, David N. Cooper and Meena Upadhyaya

A guide for functional analysis of BRCA1 variants of uncertain significance
Gaël A. Millot, Marcelo A. Carvalho, Sandrine M. Caputo, Maaike P.G. Vreeswijk, Melissa A. Brown, Michelle Webb, Etienne Rouleau, Susan L. Neuhausen, Thomas v. O. Hansen, Alvaro Galli, Rita D. Brandão, Marinus J. Blok, Aneliya Velkova, Fergus J. Couch and Alvaro N.A. Monteiro, on behalf of the ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) Consortium Functional Assay Working Group

Comprehensive functional assessment of Mlh1 variants of unknown significance
Ester Borràs, Marta Pineda, Angela Brieger, Inga Hinrichsen, Carolina Gómez, Matilde Navarro, Judit Balmaña, Teresa Ramón y Cajal, Asunción Torres, Joan Brunet, Ignacio Blanco, Guido Plotz, Conxi Lázaro and Gabriel Capellá

A novel classification system to predict the pathogenic effects of CHD7 missense variants in CHARGE syndrome
Jorieke E.H. Bergman, Nicole Janssen, Almer M. van der Sloot, Hermien E.K. de Walle, Jeroen Schoots, Nanna D. Rendtorff, Lisbeth Tranebjærg, Lies H. Hoefsloot, Conny M.A. van Ravenswaaij-Arts and Robert M.W. Hofstra

Classification of mismatch repair gene missense variants with PON-MMR
Heidi Ali, Ayodeji Olatubosun, Mauno Vihinen

Hansa: An automated method for discriminating disease and neutral human nsSNPs
Vishal Acharya, Hampapathalu A. Nagarajaram

ENIGMA—Evidence-based network for the interpretation of germline mutant alleles: An international initiative to evaluate risk and clinical significance associated with sequence variation in BRCA1 and BRCA2 genes
Amanda B. Spurdle, Sue Healey, Andrew Devereau, Frans B. L. Hogervorst, Alvaro N. A. Monteiro, Katherine L. Nathanson, Paolo Radice, Dominique Stoppa-Lyonnet, Sean Tavtigian, Barbara Wappenschmidt, Fergus J. Couch, David E. Goldgar, on behalf of ENIGMA

A review of a multifactorial probability-based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS)
Noralane M. Lindor, Lucia Guidugli, Xianshu Wang, Maxime P. Vallée, Alvaro N. A. Monteiro, Sean Tavtigian, David E. Goldgar, Fergus J. Couch

Classification of missense substitutions in the BRCA genes: A database dedicated to Ex-UVs
Maxime P. Vallée, Tiana C. Francy, Megan K. Judkins, Davit Babikyan, Fabienne Lesueur, Amanda Gammon, David E. Goldgar, Fergus J. Couch, Sean V. Tavtigian


A comparative analysis approach to determining the pathogenicity of mitochondrial tRNA mutations
John W. Yarham, Mazhor Al-Dosary, Emma L. Blakely, Charlotte L. Alston, Robert W. Taylor, Joanna L. Elson and Robert McFarland

Classifying variants of CDKN2A using computational and laboratory studies
Peter J. Miller, Sekhar Duraisamy, Joan A. Newell, Philip A. Chan, Mark M. Tie, Amy E. Rogers, Claire K. Ankuda, Genevieve M. von Walstrom, Jeffrey P. Bond and Marc S. Greenblatt

Splicing and multifactorial analysis of intronic BRCA1 and BRCA2 sequence variants identifies clinically significant splicing aberrations up to 12 nucleotides from the intron/exon boundary
Phillip J. Whiley, Lucia Guidugli, Logan C. Walker, Sue Healey, Bryony A. Thompson, Sunil R. Lakhani, Leonard M. Da Silva, kConFab Investigators, Sean V. Tavtigian, David E. Goldgar, Melissa A. Brown, Fergus J. Couch and Amanda B. Spurdle

Performance of mutation pathogenicity prediction methods on missense variants
Janita Thusberg, Ayodeji Olatubosun, and Mauno Vihinen

Functional assessment of variants in the TSC1 and TSC2 genes identified in individuals with Tuberous Sclerosis Complex
Marianne Hoogeveen-Westerveld, Marjolein Wentink, Diana van den Heuvel, Melika Mozaffari, Rosemary Ekong, Sue Povey, Johan T. den Dunnen, Kay Metcalfe, Stephanie Vallee, Stefan Krueger, JoAnn Bergoffen, Vandana Shashi, Frances Elmslie, David Kwiatkowski, Julian Sampson, Concha Vidales, Jacinta Dzarir, Javier Garcia-Planells, Kira Dies, Anneke Maat-Kievit, Ans van den Ouweland, Dicky Halley, and Mark Nellist

Verification of the three-step model in assessing the pathogenicity of mismatch repair gene variants
Minttu Kansikas, Reetta Kariola, Minna Nyström

pfSNP: An integrated potentially functional SNP resource that facilitates hypotheses generation through knowledge syntheses
Jingbo Wang, Mostafa Ronaghi, Samuel S. Chong, and Caroline G.L. Lee


MicroSNiPer: a web tool for prediction of SNP effects on putative microRNA targets
Maxim Barenboim, Brad J. Zoltick, Yongjian Guo, and Daniel R. Weinberger

Computational analysis of missense mutations causing Snyder-Robinson syndrome
Zhang Z, Teng S, Wang L, Schwartz CE, Alexov E

MUT-TP53 2.0: a novel versatile matrix for statistical analysis of TP53 mutations in human cancer
Soussi T, Hamroun D, Hjortsberg L, Rubio-Nevado JM, Fournier JL, Béroud C

Identification of Lynch syndrome mutations in the MLH1–PMS2 interface that disturb dimerization and mismatch repair
Kosinski J, Hinrichsen I, Bujnicki JM, Friedhoff P, Plotz G

Dissecting the pathogenic mechanisms of mutations in the pore region of the human cone photoreceptor cyclic nucleotide-gated channel
Koeppen K, Reuter P, Ladewig T, Kohl S, Baumann B, Jacobson SG, Plomp AS, Hamel CP, Janecke AR, Wissinger B

Cystathionine β-synthase mutations: effect of mutation topology on folding and activity
Kožich V, Sokolová J, Klatovská V, Krijt J, Janošík M, Jelínek K, Kraus JP

Understanding carbamoyl-phosphate synthetase I (CPS1) deficiency by using expression studies and structure-based analysis
Pekkala S, Martínez AI, Barcelona B, Yefimenko I, Finckh U, Rubio V, Cervera J

Performance of protein stability predictors
Khan S, Vihinen M

Predicting functional significance of cancer-associated p16INK4a mutations in CDKN2A
McKenzie HA, Fung C, Becker TM, Irvine M, Mann GJ, Kefford RF, Rizos H

Nasal epithelial cells are a reliable source to study splicing variants in Usher syndrome
Vaché C, Besnard T, Blanchet C, Baux D, Larrieu L, Faugère V, Mondain M, Hamel C, Malcolm S, Claustres M, Roux A

Functionality of sequence variants in the genes coding for the low-density lipoprotein receptor and apolipoprotein B in individuals with inherited hypercholesterolemia
Huijgen R, Kindt I, Fouchier SW, Defesche JC, Hutten BA, Kastelein JJP, Vissers MN

Genes, mutations and human inherited disease at the dawn of the age of personalized genomics
Cooper DN, Chen J, Ball EV, Howells K, Mort M, Phillips AD, Chuzhanova N, Krawczak M, Kehrer-Sawatzki H, Stenson PD

Functional evaluation of paraplegin mutations by a yeast complementation assay
Bonn F, Pantakani K, Shoukier M, Langer T, Mannan AU

Quantifying the effect of sequence variation on regulatory interactions
Manke T, Heinig M, Vingron M

Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study
Borg A, Haile RW, Malone KE, Capanu M, Diep A, Törngren T, Teraoka S, Begg CB, Thomas DC, Concannon P, Mellemkjaer L, Bernstein L, Tellhed L, Xue S, Olson ER, Liang X, Dolle J, Børresen-Dale A, Bernstein JL

Ex vivo splicing assays of mutations at noncanonical positions of splice sites in USHER genes
Le Guédard-Méreuze S, Vaché C, Baux D, Faugère V, Larrieu L, Abadie C, Janecke A, Claustres M, Roux A, Tuffery-Giraud S

In silico functional profiling of human disease-associated and polymorphic amino acid substitutions
Mort M, Evani US, Krishnan VG, Kamati KK, Baenziger PH, Bagchi A, Peters BJ, Sathyesh R, Li B, Sun Y, Xue B, Shah NH, Kann MG, Cooper DN, Radivojac P, Mooney S

Inferring the functional effects of mutation through clusters of mutations in homologous proteins
Yue P, Forrest WF, Kaminker JS, Lohr S, Zhang Z, Cavet G

A cell-free assay for the functional analysis of variants of the mismatch repair protein MLH1
Drost M, Zonneveld JBM, van Dijk L, Morreau H, Tops CM, Vasen HFA, Wijnen JT, de Wind N

Bayes analysis provides evidence of pathogenicity for the BRCA1 c.135-1G>T (IVS3-1) and BRCA2 c.7977-1G>C (IVS17-1) variants displaying in vitro splicing results of equivocal clinical significance
Spurdle AB, Lakhani SR, Da Silva LM, Balleine RL, kConFab Investigators, Goldgar DE

MUTYH mutations associated with familial adenomatous polyposis: functional characterization by a mammalian cell-based assay
Molatore S, Russo MT, D'gostino VG, Barone F, Matsumoto Y, Albertini AM, Minoprio A, Degan P, Mazzei F, Bignami M, Ranzani GN

SM2PH-db: an interactive system for the integrated analysis of phenotypic consequences of missense mutations in proteins involved in human genetic diseases
Friedrich A, Garnier N, Gagnière N, Nguyen H, Albou L, Biancalana V, Bettler E, Delèage G, Lecompte O, Muller J, Moras D, Mandel J, Toursel T, Moulinier L, Poch O

Allelic imbalance (AI) identifies novel tissue-specific cis-regulatory variation for human UGT2B15
Sun C, Southard C, Witonsky DB, Olopade OI, Di Rienzo A

Single nucleotide differences (SNDs) in the dbSNP database may lead to errors in genotyping and haplotyping studies
Musumeci L, Arthur JW, Cheung FSG, Hoque A, Lippman S, Reichardt JKV


Functional redundancy of exon 12 of BRCA2 revealed by a comprehensive analysis of the BRCA2 variant c.6853A>G, p.I2285V
Li L, Biswas K, Habib LA, Kuznetsov SG, Hamel N, Kirchoff T, Wong N, Armel S, Chong G, Narod SA, Claes K, Offit K, Robson ME, Stauffer S, Sharan SK, Foulkes WE

SMC1A expression and mechanism of pathogenicity in probands with X-Linked Cornelia de Lange syndrome
Liu J, Feldman R, Zhang Z, Deardorff MA, Haverfield EV, Kaur M, Li JR, Clark D, Kline AD, Waggoner DJ, Das S, Jackson LG, Krantz ID

Sequence contexts that determine the pathogenicity of base substitutions at position +3 of donor splice-sites
Le Guédard-Méreuze S, Vaché C, Molinari N, Vaudaine J, Claustres M, Roux A, Tuffery-Giraud S

Functional annotations improve the predictive score of human disease-related mutations in proteins
Calabrese R, Capriotti E, Fariselli P, Martelli PL, Casadio R

Modeling ATM mutant proteins from missense changes confirms retained kinase activity
Barone G, Groom A, Reiman A, Srinivasan V, Byrd PJ, Taylor AMR

Prediction of function changes associated with single-point protein mutations using support vector machines (SVMs)
Gao S, Zhang N, Duan GY, Yang Z, Ruan JS, Zhang T

Predicting the pathogenicity of RPE65 mutations
Philp AR, Jin M, Li S, Schindler EI, Iannaccone A, Lam BL, Weleber RG, Fishman GA, Jacobson SG, Mullins RF, Travis GH, Stone EM

UMD-predictor, a new prediction tool for nucleotide substitution pathogenicity – application to four genes: FBN1, FBN2, TGFBR1, and TGFBR2
Frédéric MY, Lalande M, Boileau C, Hamroun D, Claustres M, Béroud C, Collod-Béroud G

Classifying MLH1 and MSH2 variants using bioinformatic prediction, splicing assays, segregation, and tumor characteristics
Arnold S, Buchanan DD, Barker M, Jaskowski L, Walsh MD, Birney G, Woods MO, Hopper JL, Jenkins MA, Brown MA, Tavtigian SV, Goldgar DE, Young JP, Spurdle AB

The proportion of mutations predicted to have a deleterious effect differs between gain and loss of function genes in neurodegenerative disease
Valdmanis PN, Verlaan DJ, Rouleau GA

Functional and computational assessment of missense variants in the ataxia-telangiectasia mutated (ATM) gene: mutations with increased cancer risk
Mitui M, Nahas SA, Du LT, Yang Z, Lai CH, Nakamura K, Arroyo S, Scott S, Purayidom A, Concannon P, Lavin M, Gatti RA


A large fraction of unclassified variants of the mismatch repair genes MLH1 and MSH2 is associated with splicing defects
Tournier I, Vezain M, Martins A, Charbonnier F, Baert-Desurmont S, Olschwang S, Wang Q, Buisine MP, Soret J, Tazi J, Frébourg T, Tosi M

Mechanisms of pathogenicity in human MSH2 missense mutants
Ollila S, Bebek DD, Jiricny J, Nyström M

Classification of rare missense substitutions, using risk surfaces, with genetic- and molecular-epidemiology applications
Tavtigian SV, Byrnes GB, Goldgar DE, Thomas A

In silico analysis of missense substitutions using sequence-alignment based methods
Tavtigian SV, Greenblatt MS, Lesueur F, Byrnes GB; IARC Unclassified Genetic Variants Working Group

Assessment of functional effects of unclassified genetic variants
Couch FJ, Rasmussen LJ, Hofstra R, Monteiro AN, Greenblatt MS, de Wind N; IARC Unclassified Genetic Variants Working Group

Prediction and assessment of splicing alterations: implications for clinical testing
Spurdle AB, Couch FJ, Hogervorst FB, Radice P, Sinilnikova OM; IARC Unclassified Genetic Variants Working Group

Tumor characteristics as an analytic tool for classifying genetic variants of uncertain clinical significance
Hofstra RM, Spurdle AB, Eccles D, Foulkes WD, de Wind N, Hoogerbrugge N, Hogervorst FB; IARC Unclassified Genetic Variants Working Group

Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results
Plon SE, Eccles DM, Easton D, Foulkes WD, Genuardi M, Greenblatt MS, Hogervorst FB, Hoogerbrugge N, Spurdle AB, Tavtigian SV; IARC Unclassified Genetic Variants Working Group

Genetic evidence and integration of various data sources for classifying uncertain variants into a single model
Goldgar DE, Easton DF, Byrnes GB, Spurdle AB, Iversen ES, Greenblatt MS; IARC Unclassified Genetic Variants Working Group

MSH2 missense mutations and HNPCC syndrome: pathogenicity assessment in a human expression system
Belvederesi L, Bianchi F, Galizia E, Loretelli C, Bracci R, Catalani R, Amati M, Cellerino R

PLP1 splicing abnormalities identified in Pelizaeus-Merzbacher disease and SPG2 fibroblasts are associated with different types of mutations
Bonnet-Dupeyron MN, Combes P, Santander P, Cailloux F, Boespflug-Tanguy O, Vaurs-Barrière C

Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR)
Chao EC, Velasquez JL, Witherspoon MS, Rozek LS, Peel D, Ng P, Gruber SB, Watson P, Rennert G, Anton-Culver H, Lynch H, Lipkin SM

Sequence variation in the ATP-binding domain of the Wilson disease transporter, ATP7B, affects copper transport in a yeast model system
His G, Cullen LM, Macintyre G, Chen MM, Glerum DM, Cox DW

Classification of ambiguous mutations in DNA mismatch repair genes identified in a population-based study of colorectal cancer
Barnetson RA, Cartwright N, van Vliet A, Haq N, Drew K, Farrington S, Williams N, Warner J, Campbell H, Porteous ME, Dunlop MG


Functional analysis helps to clarify the clinical importance of unclassified variants in DNA mismatch repair genes
Ou J, Niessen RC, Lützen A, Sijmons RH, Kleibeuker JH, de Wind N, Rasmussen LJ, Hofstra RM

Interpreting missense variants: comparing computational methods in human disease genes CDKN2A, MLH1, MSH2, MECP2, and tyrosinase (TYR)
Chan PA, Duraisamy S, Miller PJ, Newell JA, McBride C, Bond JP, Raevaara T, Ollila S, Nystršm M, Grimm AJ, Christodoulou J, Oetting WS, Greenblatt MS