Table 2.
The unclassified variants in the present study: epidemiological and biochemical criteria
| 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 |
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 [11,12,32-35]. 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.