title: A simple method for co-segregation analysis to evaluate the pathogenicity of unclassified variants; BRCA1 and BRCA2 as an example.
abstract: BACKGROUND
  Assessment of the clinical significance of unclassified variants (UVs) identified in BRCA1 and BRCA2 is very important for genetic counselling. The analysis of co-segregation of the variant with the disease in families is a powerful tool for the classification of these variants. Statistical methods have been described in literature but these methods are not always easy to apply in a diagnostic setting.
  
  
  METHODS
  We have developed an easy to use method which calculates the likelihood ratio (LR) of an UV being deleterious, with penetrance as a function of age of onset, thereby avoiding the use of liability classes. The application of this algorithm is publicly available http://www.msbi.nl/cosegregation. It can easily be used in a diagnostic setting since it requires only information on gender, genotype, present age and/or age of onset for breast and/or ovarian cancer.
  
  
  RESULTS
  We have used the algorithm to calculate the likelihood ratio in favour of causality for 3 UVs in BRCA1 (p.M18T, p.S1655F and p.R1699Q) and 5 in BRCA2 (p.E462G p.Y2660D, p.R2784Q, p.R3052W and p.R3052Q). Likelihood ratios varied from 0.097 (BRCA2, p.E462G) to 230.69 (BRCA2, p.Y2660D). Typing distantly related individuals with extreme phenotypes (i.e. very early onset cancer or old healthy individuals) are most informative and give the strongest likelihood ratios for or against causality.
  
  
  CONCLUSIONS
  Although co-segregation analysis on itself is in most cases insufficient to prove pathogenicity of an UV, this method simplifies the use of co-segregation as one of the key features in a multifactorial approach considerably.
authors: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands. l.mohammadikhankahdani@erasmusmc.nl
authors: Leila
authors: L
authors: Mohammadi
authors: Maaike P
authors: MP
authors: Vreeswijk
authors: Rogier
authors: R
authors: Oldenburg
authors: Ans
authors: A
authors: van den Ouweland
authors: Jan C
authors: JC
authors: Oosterwijk
authors: Annemarie H
authors: AH
authors: van der Hout
authors: Nicoline
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authors: Hoogerbrugge
authors: Marjolijn
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authors: Ligtenberg
authors: Margreet G
authors: MG
authors: Ausems
authors: Rob B
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authors: van der Luijt
authors: Charlotte J
authors: CJ
authors: Dommering
authors: Johan J
authors: JJ
authors: Gille
authors: Senno
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authors: Verhoef
authors: Frans B
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authors: Hogervorst
authors: Theo A
authors: TA
authors: van Os
authors: Encarna
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authors: Gómez García
authors: Marinus J
authors: MJ
authors: Blok
authors: Juul T
authors: JT
authors: Wijnen
authors: Quinta
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authors: Helmer
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authors: Devilee
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authors: van Asperen
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authors: van Houwelingen
mesh_terms: D000465:Algorithms; D001943:Breast Neoplasms / Q000235:genetics*; D005192:Family Health; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D014644:Genetic Variation; D006801:Humans; D016013:Likelihood Functions; D015233:Models, Statistical; D010051:Ovarian Neoplasms / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype