Alignment/Grantham analysis of missense substitutions in BRCA1 that have been observed with two or more different known deleterious mutations
| Missense substitution | con-LR | Appropriate yes/no | Standard Grantham difference | Grantham deviations | H | P | G | P | M | M | C | B | M | G | X | T | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| s | t | G | p | m | m | f | t | d | g | l | n | |||||||||
| 8 P M | +Mdom | +Ggal | +Xlae | +Tnig | a | r | O | y | u | u | a | a | o | a | a | I | ||||
| p | o | R | g | l | s | m | u | m | l | e | g | |||||||||
| *Classified neutral/LCS in Goldgar et al7; †classification in Phelan et al26 meets the criteria for neutral/LCS proposed in Goldgar et al.7 | ||||||||||||||||||||
| Hsap, Homo sapiens; Ptro, Pan troglodytes; Ggor, Gorilla gorilla; Ppyg, Pongo pygmaeus; Mmul, Macaca mulatta; Mmus, Mus musculus; Cfam, Canis familiaris; Btau, Bos taurus; Mdom, M domestica; Ggal, G gallus; Xlae, X laevis; Tnig, T nigroviridis. * PM, eight placental mammals. | ||||||||||||||||||||
| A. Known neutral/LCS missense substitutions | ||||||||||||||||||||
| Q356R | 0.025 | No | 42.8 | 39.5 | 39.5 | 5.1 | 5.1 | 0.0 | Q | Q | Q | Q | Q | P | Q | Q | Q | K | – | – |
| D693N | 0.003 | Yes | 23.0 | 2.0 | 0.0 | 0.0 | 0.0 | 0.0 | D | D | D | D | A | A | A | A | V | N | N | H |
| K820E | <3×10−3 | Yes | 56.9 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | K | K | K | K | E | N | K | K | S | Q | – | – |
| R841W* | 0.003 | No | 101.3 | 101.3 | 85.0 | 85.0 | 85.0 | 78.3 | R | R | R | Q | Q | Q | Q | Q | S | S | Q | T |
| Y856H | 0.025 | Yes | 83.3 | 68.0 | 68.0 | 68.0 | 0.0 | 0.0 | Y | Y | Y | Y | Y | Y | C | Y | Y | Y | H | Q |
| P871L | 2.568 | Yes | 97.8 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | P | L | L | L | L | L | L | L | L | L | L | L |
| E1038G | 0.003 | Yes | 97.9 | 97.9 | 81.1 | 81.1 | 0.0 | 0.0 | E | E | E | E | E | E | E | E | V | R | – | S |
| S1040N | <3×10−3 | No | 46.2 | 45.8 | 2.0 | 2.0 | 2.0 | 0.0 | S | S | S | S | S | G | G | S | D | G | – | K |
| S1140G | <3×10−3 | Yes | 55.3 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | S | S | S | S | S | G | S | R | T | H | – | – |
| K1183R | <3×10−3 | Yes | 26.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | K | R | R | R | R | R | S | K | Q | K | – | G |
| R1347G | 0.003 | Yes | 125.1 | 103.5 | 81.1 | 0.0 | 0.0 | 0.0 | R | R | R | R | R | M | R | R | E | – | R | – |
| S1512I | 0.003 | No | 141.8 | 113.0 | 113.0 | 95.4 | 50.7 | 50.7 | S | S | S | S | S | G | S | S | S | P | K | E |
| S1613G | <3×10−3 | Yes | 55.3 | 28.4 | 28.4 | 0.0 | 0.0 | 0.0 | S | S | S | S | S | A | S | N | T | – | F | – |
| M1628T† | <3×10−3 | Yes | 81.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | M | M | M | M | M | V | S | R | R | – | K | – |
| M1652I | 0.003 | Yes | 10.1 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | M | M | M | M | L | M | M | M | L | I | F | L |
| B. Unclassified missense substitutions | ||||||||||||||||||||
| Y105C | 0.003 | No | 193.7 | 191.7 | 131.3 | 131.3 | 131.3 | 131.3 | Y | Y | Y | Y | Y | F | Y | Y | Q | R | Q | L |
| Y179C | 0.025 | No | 193.7 | 193.7 | 193.7 | 184.1 | 184.1 | 0.0 | Y | Y | Y | Y | Y | Y | Y | Y | Y | L | F | – |
| S186Y | 2.568 | No | 143.1 | 143.1 | 143.1 | 143.1 | 143.1 | 116.0 | S | S | S | S | S | S | S | S | S | S | S | – |
| L246V | 0.025 | Yes | 30.9 | 30.9 | 0.0 | 0.0 | 0.0 | 0.0 | L | L | L | L | L | L | L | L | V | L | – | A |
| F486L | <3×10−3 | Yes | 21.8 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | F | F | F | F | L | F | C | F | V | T | L | F |
| R496H | <3×10−3 | Yes | 28.8 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | R | R | R | R | R | Q | H | Q | H | G | G | N |
| R504H | 0.003 | Yes | 28.8 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | R | R | R | R | R | R | H | C | R | R | S | – |
| N550H | <3×10−3 | No | 68.4 | 65.5 | 65.5 | 40.5 | 13.2 | 0.0 | N | N | N | N | N | S | N | S | N | – | E | R |
| L668F | 0.251 | No | 21.8 | 21.8 | 21.8 | 21.8 | 21.3 | 21.3 | L | L | L | L | L | L | L | L | L | L | M | G |
| V772A | 0.251 | No | 65.3 | 65.3 | 65.3 | 1.0 | 1.0 | 1.0 | V | V | V | V | V | V | V | V | V | S | D | V |
| M1008V | <3×10−3 | Yes | 20.5 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | M | M | M | M | V | S | M | T | I | L | N | K |
| M1008I | <3×10−3 | Yes | 10.1 | 10.1 | 0.0 | 0.0 | 0.0 | 0.0 | M | M | M | M | V | S | M | T | I | L | N | K |
| E1060A | 0.251 | No | 106.7 | 106.7 | 77.3 | 77.3 | 51.8 | 0.0 | E | E | E | E | E | E | E | E | K | E | – | – |
| E1250K | 0.025 | Yes | 56.9 | 51.6 | 51.6 | 34.4 | 0.0 | 0.0 | E | E | E | E | E | Q | E | E | E | – | K | – |
| D1546N | 0.025 | Yes | 23.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | D | D | D | D | D | N | D | D | – | – | D | – |
| L1564P | 0.025 | Yes | 97.8 | 97.8 | 0.0 | 0.0 | 0.0 | 0.0 | L | L | L | L | L | L | L | L | P | – | L | N |
| P1637L | 0.025 | No | 97.8 | 97.8 | 97.8 | 63.6 | 63.6 | 63.6 | P | P | P | P | P | P | P | P | S | E | P | E |
| D1733G | 0.025 | No | 93.8 | 75.3 | 75.3 | 56.4 | 56.4 | 51.7 | D | D | D | D | D | E | D | D | D | H | D | L |