Table 1.
Tumor sequencing data for 69 tumors from individuals heterozygous for a germline LoF (n = 41) or MS (n = 29) variant in a known breast cancer predisposition gene (BARD1, BRIP1, CHEK2, and RAD51D)
| IDa | Gene | Germline variant | Variant type | Variant allelic statusb | BC subtype | HRD | Somatic TP53 | Somatic PIK3CA | Mutation signature 3c | Dominant mutation signature | Promoter hypermethylation |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 3530 | BARD1 | c.1135A>T, p.Lys379Ter | LoF | Mutant loss | ER+/HER2- | na | na | na | na | na | Failed |
| 3977 | BARD1 | c.1212C>G, p.Tyr404Ter | LoF | WT loss | TN | 50 | na | na | Strong | 3, 11 | DNT |
| 1531 | BARD1 | c.1652C>G, p.Ser551Ter | LoF | WT loss | TN | 83 | LoF | — | Weak | 19, 30 | DNT |
| 3828 | BARD1 | c.1652C>G, p.Ser551Ter | LoF | WT loss | TN | 92 | MS | — | Strong | 1, 3 | DNT |
| 425 | BARD1 | c.1652C>G, p.Ser551Ter | LoF | LOH | TN | 80 | na | na | Strong | na | |
| 3496 | BARD1 | c.1905G>A, p.Trp635Ter | LoF | Het | TN | 82 | MS | — | Strong | 3 | Failed |
| 1272 | BARD1 | c.2078_2079insTAATA, p.Lys693AsnfsTer23 | LoF | WT loss | TN | 76 | LoF | — | No | 19 | DNT |
| 2439 | BRIP1 | c.93 + 1G>T | LoF | WT loss | TN | 59 | LoF | — | Strong | 3, 19 | DNT |
| 4160 | BRIP1 | c.103G>T, p.Gly35Ter | LoF | Mutant loss | ER-/HER2+ | 30 | MS | — | Strong | 1, 3 | na |
| 3259 | BRIP1 | c.1426del, p.Thr476LeufsTer50 | LoF | WT loss | ER+/HER2- | 41 | — | MS | No | 12, 20 | DNT |
| 3597 | BRIP1 | c.1888dup, p.Thr630AsnfsTer9 | LoF | Het | ER+/HER2- | 12 | — | MS | No | 30 | Negative |
| 3093 | BRIP1 | c.2298_2301delTGAG, p.Ser766ArgfsTer14 | LoF | Het | ER+/HER2- | 5 | — | MS | na | na | na |
| 227 | BRIP1 | c.2392C>T, p.Arg798Ter | LoF | WT loss | TN | 58 | MS | — | No | 20, 21 | DNT |
| 1325 | BRIP1 | c.2392C>T, p.Arg798Ter | LoF | Mutant loss | TN | 57 | LoF | — | na | na | na |
| 786 | BRIP1 | c.2392C>T, p.Arg798Ter | LoF | Het | ER+/HER2- | 1 | LoF | — | na | na | Failed |
| 1928 | BRIP1 | c.2392C>T, p.Arg798Ter | LoF | Het | ER+/HER2- | 11 | MS | — | na | na | Negative |
| 3829 | BRIP1 | c.2400C>G, p.Tyr800Ter | LoF | Mutant loss | TN | 50 | — | — | Weak | 6 | na |
| 3635 | BRIP1 | c.2400C>G, p.Tyr800Ter | LoF | Het | ER+/HER2- | 32 | LoF | — | Weak | 1 | na |
| 3354 | BRIP1 | c.2492_2492 + 5delGGTAAG | LoF | WT loss | ER+/HER2- | 31 | MS | MS | Weak | 1 | DNT |
| 3468 | BRIP1 | c.3715del, p.Ser1239ProfsTer15 | LoF | Mutant loss | ER+/HER2- | 37 | LoF | — | Weak | 1, 13 | na |
| 4152 | CHEK2 | c.629_732delCAGT, p.Ser210PhefsTer6 | LoF | Mutant loss | ER+/HER2- | 47 | MS | — | No | 3 | Negative |
| 2320 | CHEK2 | c.630delA, p.Val211PhefsTer6 | LoF | Het | na | 7 | — | — | Weak | 5, 30 | na |
| 290 | CHEK2 | c.902delT, p.Leu301TrpfsTer3 | LoF | Mutant loss | ER+/HER2- | 27 | — | — | Weak | 1,6 | na |
| 3587 | CHEK2 | c.1100delC, p.Thr367MetfsTer15 | LoF | WT loss | ER+/HER2- | 34 | na | na | No | 11 | DNT |
| 1825 | CHEK2 | c.1100delC, p.Thr367MetfsTer15 | LoF | Het | ER+/HER2- | 32 | LoF | — | Strong | 3 | na |
| 3174 | CHEK2 | c.1100delC, p.Thr367MetfsTer15 | LoF | Het | ER+/HER2- | 29 | — | — | No | 6, 30 | na |
| 2182 | CHEK2 | c.1100delC, p.Thr367MetfsTer15 | LoF | Het | ER+/HER2- | 45 | — | — | No | 11, 19 | Failed |
| 2410 | CHEK2 | c.1100delC, p.Thr367MetfsTer15 | LoF | Het | ER+/HER2- | 27 | — | — | No | 1, 30 | Failed |
| 2475 | CHEK2 | c.1100delC, p.Thr367MetfsTer15 | LoF | WT loss | ER+/HER2- | 80 | — | — | No | 6, 19 | DNT |
| 1300 | CHEK2 | c.1100delC, p.Thr367MetfsTer15 | LoF | WT loss | ER+/HER2- | 36 | — | MS | No | 10 | Failed |
| 2326 | CHEK2 | c.1100delC, p.Thr367MetfsTer15 | LoF | WT loss | ER+/HER2- | 21 | — | — | No | 19, 30 | Failed |
| 2711 | CHEK2 | c.1100delC, p.Thr367MetfsTer15 | LoF | WT loss | ER+/HER2+ | 10 | — | — | No | 1, 11 | Failed |
| 3500 | CHEK2 | c.1100delC, p.Thr367MetfsTer15 | LoF | Het | ER+/HER2unknown | 37 | — | — | Strong | 3 | na |
| 2351 | CHEK2 | c.1100delC, p.Thr367MetfsTer15 | LoF | Het | ER-/HER2+ | 4 | na | na | Weak | 19, 30 | DNT |
| 3076 | CHEK2 | c.1100delC, p.Thr367MetfsTer15 | LoF | Het | ER-/HER2+ | 1 | — | — | No | 1 | na |
| 1732 | CHEK2 | c.1100delC, p.Thr367MetfsTer15 | LoF | WT Loss | TN | 17 | MS | MS | No | 6 | DNT |
| 1853 | CHEK2 | c.1696delC, p.Thr533GlnfsTer33 | LoF | Het | ER+/HER2- | 28 | MS | — | na | na | na |
| 2625 | CHEK2 | c.14C>T, p.Ser5Leu | MS | Het | ER+/HER2- | 85 | — | — | Weak | 19 | Failed |
| 1993 | CHEK2 | c.190G>A, p.Glu64Lys | MS | Het | ER+/HER2- | 91 | LoF | — | Weak | 1, 6 | na |
| 811 | CHEK2 | c.349A>G, p.Arg117Gly | MS | Het | ER+/HER2+ | 0 | — | MS | Weak | 5 | Negative |
| 1103 | CHEK2 | c.349A>G, p.Arg117Gly | MS | Mutant loss | ER+/HER2- | 16 | — | MS | Weak | 3 | Negative |
| 616 | CHEK2 | c.349A>G, p.Arg117Gly | MS | Het | ER-/HER2+ | 17 | — | MS | Strong | 1, 3 | na |
| 787 | CHEK2 | c.442A>G, p.Arg148Gly | MS | Het | ER+/HER2- | na | na | na | na | na | Failed |
| 2531 | CHEK2 | c.470T>C, p.Ile157Thr | MS | Het | ER+/HER2- | 34 | — | — | Weak | 19 | Negative |
| 1420 | CHEK2 | c.470T>C, p.Ile157Thr | MS | Het | ER+/HER2- | 28 | MS | MS | No | 6 | Negative |
| 3240 | CHEK2 | c.470T>C, p.Ile157Thr | MS | Het | ER+/HER2- | 16 | — | — | Strong | 3, 6 | na |
| 807 | CHEK2 | c.1036C>T, p.Arg346Cys; c.499G>A, p. Gly167Arg | MS MS |
WT loss; mutant loss | ER+/HER2unknown | 52 | — | — | Weak | 1 | na |
| 2091 | CHEK2 | c.1067C>T, p.Ser356Leu | MS | Het | ER+/HER2- | 47 | — | — | Weak | 1, 19 | Failed |
| 2689 | CHEK2 | c.1211A>G, p.Tyr404Cys | MS | WT loss | ER+/HER2+ | 28 | — | MS | Strong | 3, 30 | DNT |
| 2221 | CHEK2 | c.1270T>C, p.Tyr424His | MS | WT loss | ER+/HER2- | 13 | — | MS | No | 20 | DNT |
| 1830 | CHEK2 | c.1312G>T, p.Asp438Tyr | MS | Het | ER+/HER2- | 17 | — | — | na | na | na |
| 2257 | CHEK2 | c.1312G>T, p.Asp438Tyr | MS | Het | ER+/HER2- | 0 | — | MS | Weak | 6 | Negative |
| 200 | CHEK2 | c.1312G>T, p.Asp438Tyr | MS | Het | na | 5 | — | — | Strong | 3 | na |
| 4164 | CHEK2 | c.1427C>T, p.Thr476Met | MS | Het | ER+/HER2- | 13 | — | — | No | 11, 19 | na |
| 1410 | CHEK2 | c.1447C>T, p.His483Tyr | MS | Mutant loss | ER+/HER2- | 30 | MS | — | na | na | DNT |
| 2345 | CHEK2 | c.1525C>T, p.Pro509Ser | MS | Mutant loss | ER+/HER2+ | 7 | LoF | — | na | na | Negative |
| 1198 | CHEK2 | c.1604G>A, p.Arg535His | MS | Het | TN | 22 | MS | — | No | 6, 30 | Failed |
| 1897 | RAD51D | c.616C>T, p.Arg206Ter | LoF | Het | ER+/HER2- | 4 | — | — | na | na | Negative |
| 2734 | RAD51D | c.754C>T, p.Arg252Ter | LoF | WT loss | TN | 42 | LoF | — | na | na | DNT |
| 2866 | RAD51D | c.808delC, p.His270ThrfsTer2 | LoF | Het | TN | 7 | — | — | na | na | na |
| 3500 | RAD51D | c.863G>A, p.Trp288Ter | LoF | Het | ER+/HER2- | 8 | — | — | Weak | 30 | na |
| 506 | RAD51D | c.26G>C, p.Cys9Ser | MS | Het | ER+/HER2- | 0 | — | — | na | na | na |
| 30 | RAD51D | c.26G>C, p.Cys9Ser | MS | Het | ER+/HER2- | 20 | MS | — | na | na | na |
| 2936 | RAD51D | c.26G>C, p.Cys9Ser | MS | Het | ER+/HER2- | 8 | — | — | No | 5 | DNT |
| 1980 | RAD51D | c.26G>C, p.Cys9Ser | MS | Het | TN | 3 | LoF | — | No | 1 | Negative |
| 2224 | RAD51D | c.137C>G, p.Ser46Cys | MS | Het | ER+/HER2- | 4 | — | — | na | na | Negative |
| 2219 | RAD51D | c.155C>T, p.Ala52Val; c.938C>T, p. Ala313Val | MS compound homozygous | WT loss; mutant loss | TN | 42 | LoF | — | Strong | 3 | Negative |
| 1686 | RAD51D | c.308C>T, p.Ala103Val | MS | Het | TN | 17 | MS | — | na | na | Negative |
| 3095 | RAD51D | c.472A>C, p.Asn158His | MS | Mutant Loss | ER+/HER2+ | 20 | — | — | na | na | na |
| 2606 | RAD51D | c.551T>C, p.Leu184Pro | MS | WT Loss | ER+/HER2- | 11 | MS | — | na | na | DNT |
a
Subject 3093 carried 2 variants of interest in BRIP1; subject 2219 carried 2 variants in RAD51C; subject 3500 carried a variant of interest in both CHEK2 and RAD51D. “—” signifies feature not present. BC = breast cancer; DNT = did not test; na = not available; ER+ = estrogen receptor—positive breast cancer; HER2- = HER2 negative; HER2+ = HER2 positive; HRD = homologous recombination deficiency score; LoF = loss of function; MS = missense; TN = triple-negative; WT = wild type.
b
WT loss, somatic loss of the WT allele; mutant loss, somatic loss of the allele carrying the known germline variant; Het, heterozygous. Case 425 showed loss of heterozygosity across the gene regions but unable to determine which allele had been lost.
c
Proportion of mutational signature 3 (COSMIC v2, assessed on whole-exome sequenced tumors only) above 25% is classified as “strong”, under 25% as “weak”.