Table 2.
Mutations and likely deleterious variants, their effect on splicing or protein, cancer history of carriers
| Gene | Genetic variation | Variant class | Effect on splicing | Predicted effect on protein (Align-GVGD class † ) | Personal cancer history (age at diagnosis) | Family cancer history (age at diagnosis) | Controls ‡ |
|---|---|---|---|---|---|---|---|
|
RAD51B |
c.452 + 3A > G |
Splicing mutation |
Exon 5 skipping by in silico prediction* |
Unstable or truncated protein, confirmed by negative IHC |
BC (34) |
Paternal aunt, BC (58); 3rd degree relative, OC (29) |
- |
|
RAD51B |
c.475C > T, p. Arg159Cys |
Likely deleterious missense variant |
No predicted effect |
ATP-binding domain, highly conserved amino acid, Grantham 180 (Class C65) |
BC (54) |
Sister, BC (45); Sister’s daughter BC (45) |
2/4299 |
|
RAD51C |
c.706-2A > G |
Splicing mutation |
Exon 5 skipping confirmed by mRNA analysis |
44 amino acids loss in ATP-binding domain |
BC (39) |
Paternal aunt§, OC (67) |
- |
|
RAD51C |
c.1026 + 5_1026 + 7del |
Splicing mutation |
Exon 8 skipping confirmed by mRNA analysis |
Unstable or truncated protein |
BC (38), OC (51) |
Father, PC (69); Paternal grandmother, UC (66); Paternal grandfather, SC (69) |
- |
| XRCC3 | c.448C > T, p. Arg150Cys | Likely deleterious missense variant | No predicted effect | ATP-binding domain, highly conserved amino acid, Grantham 180 (Class C65) | BC (63) | Mother, OC (61); Maternal aunt, BC (55); Maternal aunt, BC (73); Maternal aunt, BC (76); Maternal aunt, BC (63, 79) | 1/4276 |
BC: Breast cancer, OC: Ovarian cancer, PC: Pancreas cancer, UC: Uterine cancer, SC: Stomach cancer.
*See text for details.
†Align-Grantham Variation Grantham Deviation (Align-GVGD) classes range from C0 to C65; C65 class variants are the most likely to interfere with protein function [22,23].
§This paternal aunt also carried the RAD51C c.706-2A > G mutation.
‡Frequency in controls in online databases: Exome Variant Server [28], dbSNP [38], 1000 Genomes [29]. The three splicing mutations have never been described. The 2 missense variants were reported only in Exome Variant Server, in European-American populations. Their frequencies in European-American populations are reported in this table.