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Table 2 The unclassified variants in the present study: epidemiological and biochemical criteria

From: A method to assess the clinical significance of unclassified variants in the BRCA1 and BRCA2genes based on cancer family history

Variant [22] Number of families Co-segregation (present study)a Polarity change Conserved mammals/other [21]b Grantham score [19] Times reported (Breast Cancer Information Core [1]) Co-segregation (literature) Co-occurrence (literature) Classification (literature) Referencec
BRCA1           
   p.L246V 2 ND No No/No 32 79 No Yes (several) Neutral [5, 7, 13]
   p.S1655F 2 6/6 (n = 2) Yes Yes/Yes 155 3 Not done Not done Deleterious [5, 32, 34, 35]
   p.R1699W 9 8/8 (n = 4) Yes Yes/Yes 101 13 Not done No Deleterious [1, 14, 35]
   p.R1699Q 5 1/2 (n = 2)d Yes Yes/Yes 43 11 Yes No Deleterious, uncertain, low/moderate [5, 6, 9, 12, 32, 34, 35]
   Total 18          
BRCA2           
   p.Y42C 3 ND N No/No 194 14 No Yes Neutral [6, 9, 11]
   p.E462G 8 2/5 (n = 5) Yes Yes/No 98 35 No Yes (Y3097X) Neutral [11, 12]
   p.Y2660D 9 8/8 (n = 5) Yes Yes/Yes 160 2 Not done Not done   None
   p.R2784W 1 ND Yes Yes/Yes 101 5 Not done Not done Uncertain [33]
   p.R2784Q 4 1/2 (n = 2)e Yes Yes/Yes 43 4 Not done Not done   None
   p.R2888C 5 1/1 (n = 1) Yes No/Yes 180 4 No Yes Neutral [14]
   p.R3052W 10 1/1 (n = 1) Yes Yes/Yes 101 8 Not done Not done Deleterious [33]
   p.R3052Q 1 0/1 (n = 1) Yes Yes/Yes 43 3 Not done Yes Neutral [14]
   Total 41          
  1. aCo-segregation in the present study is expressed as number of tested positive (proband excluded)/total number of affected relatives tested (n = number of families tested). bAlignments based on the following species and NCBI reference sequences: BRCA1: human (NP_009225), chimp (AAG43492), gorilla (AAT44835), orang (AAT44834), macacque (AAT44833), dog (AAC48663), mouse (AAD00168), cow (NP848668), opossum (AAX92675), chicken (NP989500), xenopus (AAL13037), and pufferfish (AAR89523); and BRCA2: human (NP000050), chimp (XP509619), dog (BAB91245), mouse (AAB48306), chicken (AAL89470), and tetraodon (CAG09009). cFunctional studies were performed in [11, 12, 3235]. dLack of co-segregation was observed in one of the two pedigrees analyzed. In that pedigree, the proband had BC at age 37, her father's sister had BC at age 61, her cousin (the daughter of that aunt) had BC at age 45 – did not have the UV. eThis UV does not co-segregate with the disease in one family, which consisted of two affected members: the proband had BC at age 31, her mother with BC at age 67 – did not have the UV.