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Table 2

Prediction of the cancer phenotype of 57 functionally uncharacterized missense mutations in the human BRCA1 BRCT domains

MutationAllowed residuesaPredictionComments
M1652T MIF • Large volume change in rigid neighborhood. Found in breast and ovarian cancer families in Finland (45). 
V1653M ○ Likely amino acid substitution. 
L1664P LITM • Helix breaker. 
T1685A • Unlikely amino acid substitution at completely preserved position. 
T1685I • Unlikely amino acid substitution at completely preserved position. 
M1689R MI • Charge change, two-class polarity change. 
D1692Y • Unlikely amino acid substitution at completely preserved position. 
F1695L FL ○ Likely amino acid substitution, ′L′ allowed in MSA. 
V1696L ○ Likely amino acid substitution. 
R1699L • Predicted binding site, charge change, two-class polarity change, unlikely amino acid substitution at completely preserved position, BRCT-domain interface (8). 
G1706E • Large volume change at rigid position and in rigid neighborhood, charge change, unlikely amino acid substitution at completely preserved position. 
W1718C • Large volume change at rigid position and in rigid neighborhood, unlikely amino acid substitution at completely preserved position, BRCT signature WXXXS motif (13). 
W1718S • Large volume change at rigid position and in rigid neighborhood, unlikely amino acid substitution at completely preserved position. 
T1720A TIV ○ Likely amino acid substitution. 
N1730S NDS ○ Likely amino acid substitution, ′S′ allowed in MSA. 
F1734S • Very large volume change at flexible position, unlikely amino acid substitution at completely preserved position. 
E1735K • Charge change. Found in a family with five breast cancer patients, in first-degree relationship, over two generations (46). 
V1736A • Unlikely amino acid substitution at completely preserved position. 
G1738R • Very large volume change at flexible position, unlikely amino acid substitution at completely preserved position. Found in four unrelated patients from breast-ovarian cancer families. Segregation analysis not done (47). 
D1739E ○ Likely amino acid substitution. 
D1739G • Unlikely amino acid substitution at completely preserved position. 
D1739Y • Large volume change at rigid position, two-class polarity change, unlikely amino acid substitution at completely preserved position. 
V1741G VI ○ Likely amino acid substitution. Found in combination with another deleterious mutation (E1754X) and therefore likely to represent a benign polymorphism (48). 
H1746N • Unlikely amino acid substitution at completely preserved position. 
R1751P KR • Unlikely amino acid substitution at completely preserved position, helix breaker. 
R1751Q KR ○ Likely amino acid substitution. Found in a breast-ovarian cancer family. Segregation analysis not done (49). 
R1758G REG ○ Likely amino acid substitution, ′G′ allowed in MSA. Found in two cases with no family history (50). 
L1764P LF ○ Likely amino acid substitution. 
I1766S IV • Large volume change at rigid position. 
P1771L PS ○ Likely amino acid substitution. 
T1773S ○ Likely amino acid substitution, predicted binding site. 
P1776S PT ○ Likely amino acid substitution. Found in an ovarian cancer case but with no family history (39). 
D1778G DG • Helix breaker, ′G′ allowed in MSA. 
D1778H DG ○ Likely amino acid substitution. Found in a patient with no family history (46). 
D1778N DG ○ Likely amino acid substitution. 
M1783T MI ○ Likely amino acid substitution. 
C1787S • Unlikely amino acid substitution at completely preserved position, BRCT domain interface (8). 
G1788D • Unlikely amino acid substitution at completely preserved position, turn breaker. 
G1788V • Unlikely amino acid substitution at completely preserved position, turn breaker. Found in a bilateral breast and ovarian cancer case with family history (51). 
G1803A GN ○ Turn breaker, out of known and putative binding sites. 
V1804D VTAS • Two-class polarity change. 
V1808A • Unlikely amino acid substitution at completely preserved position. 
V1809A VLI ○ Likely amino acid substitution. 
V1809F VLI ○ Likely amino acid substitution. 
V1810G • Unlikely amino acid substitution at completely preserved position. 
Q1811R • Charge change in putative binding site. 
P1812S • Unlikely amino acid substitution at completely preserved position, predicted binding site. Found in an ovarian cancer case but with no family history (39). 
N1819S NSTR ○ Likely amino acid substitution, ′S′ allowed in multiple sequence alignment. 
A1823T ADE ○ Likely amino acid substitution. Found in one patient from a breast-ovarian cancer family. Segregation analysis not done (47). 
V1833M ○ Likely amino acid substitution. Found in one patient from a breast-ovarian cancer family. Segregation analysis not done (47). 
W1837G • Large volume change at rigid position, unlikely amino acid substitution at completely preserved position, helix breaker, BRCT signature WXXXS motif (13). 
W1837R • Charge change, two-class polarity change, unlikely amino acid substitution at completely preserved position, BRCT signature WXXXS motif (13). Found in an early onset breast cancer case. Proband’s father also had breast cancer and the mutation was found to segregate with disease (52). 
S1841N • BRCT signature WXXXS motif (13). 
A1843P AS • Helix breaker. Found in ovarian cancer family in Japan. Segregation analysis not done (44). 
T1852S TA ○ Likely amino acid substitution. 
P1856T PQS ○ Likely amino acid substitution. 
P1859R PT ○ Likely amino acid substitution. 
MutationAllowed residuesaPredictionComments
M1652T MIF • Large volume change in rigid neighborhood. Found in breast and ovarian cancer families in Finland (45). 
V1653M ○ Likely amino acid substitution. 
L1664P LITM • Helix breaker. 
T1685A • Unlikely amino acid substitution at completely preserved position. 
T1685I • Unlikely amino acid substitution at completely preserved position. 
M1689R MI • Charge change, two-class polarity change. 
D1692Y • Unlikely amino acid substitution at completely preserved position. 
F1695L FL ○ Likely amino acid substitution, ′L′ allowed in MSA. 
V1696L ○ Likely amino acid substitution. 
R1699L • Predicted binding site, charge change, two-class polarity change, unlikely amino acid substitution at completely preserved position, BRCT-domain interface (8). 
G1706E • Large volume change at rigid position and in rigid neighborhood, charge change, unlikely amino acid substitution at completely preserved position. 
W1718C • Large volume change at rigid position and in rigid neighborhood, unlikely amino acid substitution at completely preserved position, BRCT signature WXXXS motif (13). 
W1718S • Large volume change at rigid position and in rigid neighborhood, unlikely amino acid substitution at completely preserved position. 
T1720A TIV ○ Likely amino acid substitution. 
N1730S NDS ○ Likely amino acid substitution, ′S′ allowed in MSA. 
F1734S • Very large volume change at flexible position, unlikely amino acid substitution at completely preserved position. 
E1735K • Charge change. Found in a family with five breast cancer patients, in first-degree relationship, over two generations (46). 
V1736A • Unlikely amino acid substitution at completely preserved position. 
G1738R • Very large volume change at flexible position, unlikely amino acid substitution at completely preserved position. Found in four unrelated patients from breast-ovarian cancer families. Segregation analysis not done (47). 
D1739E ○ Likely amino acid substitution. 
D1739G • Unlikely amino acid substitution at completely preserved position. 
D1739Y • Large volume change at rigid position, two-class polarity change, unlikely amino acid substitution at completely preserved position. 
V1741G VI ○ Likely amino acid substitution. Found in combination with another deleterious mutation (E1754X) and therefore likely to represent a benign polymorphism (48). 
H1746N • Unlikely amino acid substitution at completely preserved position. 
R1751P KR • Unlikely amino acid substitution at completely preserved position, helix breaker. 
R1751Q KR ○ Likely amino acid substitution. Found in a breast-ovarian cancer family. Segregation analysis not done (49). 
R1758G REG ○ Likely amino acid substitution, ′G′ allowed in MSA. Found in two cases with no family history (50). 
L1764P LF ○ Likely amino acid substitution. 
I1766S IV • Large volume change at rigid position. 
P1771L PS ○ Likely amino acid substitution. 
T1773S ○ Likely amino acid substitution, predicted binding site. 
P1776S PT ○ Likely amino acid substitution. Found in an ovarian cancer case but with no family history (39). 
D1778G DG • Helix breaker, ′G′ allowed in MSA. 
D1778H DG ○ Likely amino acid substitution. Found in a patient with no family history (46). 
D1778N DG ○ Likely amino acid substitution. 
M1783T MI ○ Likely amino acid substitution. 
C1787S • Unlikely amino acid substitution at completely preserved position, BRCT domain interface (8). 
G1788D • Unlikely amino acid substitution at completely preserved position, turn breaker. 
G1788V • Unlikely amino acid substitution at completely preserved position, turn breaker. Found in a bilateral breast and ovarian cancer case with family history (51). 
G1803A GN ○ Turn breaker, out of known and putative binding sites. 
V1804D VTAS • Two-class polarity change. 
V1808A • Unlikely amino acid substitution at completely preserved position. 
V1809A VLI ○ Likely amino acid substitution. 
V1809F VLI ○ Likely amino acid substitution. 
V1810G • Unlikely amino acid substitution at completely preserved position. 
Q1811R • Charge change in putative binding site. 
P1812S • Unlikely amino acid substitution at completely preserved position, predicted binding site. Found in an ovarian cancer case but with no family history (39). 
N1819S NSTR ○ Likely amino acid substitution, ′S′ allowed in multiple sequence alignment. 
A1823T ADE ○ Likely amino acid substitution. Found in one patient from a breast-ovarian cancer family. Segregation analysis not done (47). 
V1833M ○ Likely amino acid substitution. Found in one patient from a breast-ovarian cancer family. Segregation analysis not done (47). 
W1837G • Large volume change at rigid position, unlikely amino acid substitution at completely preserved position, helix breaker, BRCT signature WXXXS motif (13). 
W1837R • Charge change, two-class polarity change, unlikely amino acid substitution at completely preserved position, BRCT signature WXXXS motif (13). Found in an early onset breast cancer case. Proband’s father also had breast cancer and the mutation was found to segregate with disease (52). 
S1841N • BRCT signature WXXXS motif (13). 
A1843P AS • Helix breaker. Found in ovarian cancer family in Japan. Segregation analysis not done (44). 
T1852S TA ○ Likely amino acid substitution. 
P1856T PQS ○ Likely amino acid substitution. 
P1859R PT ○ Likely amino acid substitution. 
a

Comments list the rationalizations for each of the 57 predictions, as produced by the classification tree (Fig. 3). ○ indicates a predicted benign mutation, and • indicates a predicted cancer-associated mutation.

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