Table 2.
Sequencing results of 57 tumors from individuals heterozygous for a germline LoF (n = 43) or MS (n = 16) variant in a candidate breast cancer predisposition gene (BLM, CDK9, CTH, ERCC5, FANCM, MUTYH, PARP2, RAD50, RAD51B, WRN, and PARP2)
| IDa | Germline gene | Variant | Variant type | Variant statusb | Subtype | HRD | Somatic TP53 | Somatic PIK3CA | Mutation signature 3c | Dominant signature | Hypermutated |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 2660 | BLM | c.318_319insT, p.Leu107PhefsTer36 | LoF | Het | ER+/HER2- | 1 | — | — | na | na | Negative |
| 1471 | c.768_769delCT, p.Leu258GlufsTer7 | LoF | Mutant Loss | ER+/HER2unknown | 5 | — | MS | na | na | Negative | |
| 462 | c.1624delG, p.Asp542ThrfsTer2 | LoF | Mutant Loss | TN | 44 | LoF | — | na | na | Negative | |
| 3093 | c.2695C>T, p.Arg899Ter | LoF | Het | ER+/HER2- | 5 | — | MS | na | na | na | |
| 2287 | c.2875C>T, p.Arg959Ter | LoF | Het | ER+/HER2- | 11 | — | — | na | na | Negative | |
| 2083 | c.3210 + 2delT | LoF | Het | ER+/HER2- | 6 | — | — | na | na | Failed | |
| 35 | c.3558 + 1G>T | LoF | Het | ER+/HER2unknown | 17 | — | MS | na | na | Negative | |
| 1245 | CDK9 | c.130delA, p.Lys44ArgfsTer4 | LoF | Het | ER+/HER2- | 13 | MS | — | na | na | Failed |
| 2345 | c.274delT, p.Tyr92IlefsTer23 | LoF | Het | ER+/HER2+ | 4 | LoF | — | na | na | Negative | |
| 3075 | c.620_621insC, p.Ile210HisfsTer2 | LoF | Het | TN | 56 | LoF | — | na | na | Failed | |
| 2723 | c.689_690insG, p.Asn232GlnfsTer20 | LoF | Het | ER+/HER2+ | 0 | — | — | na | na | na | |
| 2045 | CTH | c.465G>A, p.Trp155Ter | LoF | Het | ER+/HER2- | 19 | — | — | na | na | Failed |
| 1322 | c.465G>A, p.Trp155Ter | LoF | Het | ER+/HER2+ | 20 | MS | — | na | na | Failed | |
| 3119 | c.465G>A, p.Trp155Ter | LoF | Het | ER+/HER2+ | 0 | — | — | na | na | na | |
| 1865 | c.1064delC, p.Thr355IlefsTer19 | LoF | Het | ER+/HER2- | 36 | MS | — | na | na | Failed | |
| 1092 | c.230C>T, p.Ala77Val | MS | Het | ER+/HER2- | 20 | ESS | — | No | 5, 12 | Failed | |
| 307 | c.323T>C, p.Ile108Thr | MS | Het | TN | 24 | LoF | — | na | na | Failed | |
| 2593 | c.620T>C, p.Met207Thr | MS | Het | na | 9 | — | — | na | na | na | |
| 1065 | c.718C>G, p.Gln240Glu | MS | Het | ER+/HER2- | 0 | — | — | na | na | na | |
| 4142 | c.794G>A, p.Arg265Gln | MS | Het | ER+/HER2- | 10 | LoF | — | na | na | Failed | |
| 3197 | c.1124G>A, p.Arg375Gln | MS | Het | ER+/HER2- | 19 | — | — | Weak | 1, 12 | na | |
| 2260 | ERCC5 | c.589delC, p.Pro198LeufsTer3 | LoF | Mutant Loss | TN | 41 | — | — | Weak | 15 | Failed |
| 901 | c.1774_1775insAAGCA, p.Val592GlufsTer8 | LoF | Mutant Loss | TN | 83 | — | MS | No | 11 | na | |
| 1367 | FANCM | c.2267G>A, p.Arg756His | LoF | Het | ER+/HER2- | 24 | — | MS | No | 6 | Failed |
| 1709 | c.3589delG, p.Asp1197MetfsTer18 | LoF | Mutant Loss | TN | 26 | MS | — | Weak | 6 | Failed | |
| 3147 | c.5101C>T, p.Gln1701Ter | LoF | Het | ER+/HER2- | 6 | — | — | Weak | 3, 6 | Failed | |
| 691 | c.5791C>T, p.Arg1931Ter | LoF | Het | ER+/HER2- | 2 | MS | MS | No | 6 | na | |
| 1172 | c.5791C>T, p.Arg1931Ter | LoF | Het | ER+/HER2+ | 0 | — | — | No | 1 | Failed | |
| 2771 | c.5791C>T, p.Arg1931Ter | LoF | WT Loss | TN | 18 | LoF | — | No | 1, 26 | DNT | |
| 1127 | c.163G>A, p.Asp55Asn | MS | Mutant Loss | TN | 51 | — | — | Weak | 3 | Failed | |
| 2094 | c.2267G>A, p.Arg756His | MS | Het | TN | 40 | MS | — | Strong | 1, 3 | Failed | |
| 1879 | c.2267G>A, p.Arg756His | MS cpd | Het | ER+/HER2- | 72 | LoF | — | Weak | 1, 19 | DNT | |
| 1222 | c.3998A>C, p.Gln1333Pro | MS | WT Loss | TN | 48 | LoF | — | Weak | 5 | DNT | |
| 901 | c.5108A>G, p.His1703Arg | MS | Het | TN | 83 | — | MS | No | 5 | na | |
| 2743 | MUTYH | c.925-2A>G | LoF | Het | TN | 10 | MS | — | na | na | Failed |
| 2727‡ | c.925-2A>G | LoF | Het | TN | 36 | LoF | — | na | na | Failed | |
| 1253 | c.384G>A, p.Trp128Ter | Biallelic LoF | Germline homozygous | TN | na | — | — | na | na | na | |
| 1474 | PARP2 | c.979_980insTT, p.Ser328CysfsTer8 | LoF | Mutant Loss | ER+/HER2- | 67 | — | MS | na | na | DNT |
| 2294 | c.985_986insA, p.Ile331AsnfsTer11 | LoF | Het | ER-/HER2+ | 81 | — | — | na | na | Failed | |
| 333 | c.1109_1110insT, p.Leu372ProfsTer2 | LoF | Mutant Loss | ER+/HER2- | na | — | — | na | na | na | |
| 1185 | c.1304delG, p.Val436TrpfsTer4 | LoF | Het | ER-/HER2+ | 30 | MS | MS | na | na | Failed | |
| 1327 | c.965G>A, p.Arg322Gln | MS | WT Loss | ER+/HER2- | 28 | — | — | na | na | DNT | |
| 2883 | RAD50 | c.1291_1297delGAGATAA, p.Asp434LysfsTer7 | LoF | Het | ER+/HER2- | 47 | — | — | No | 16 | Failed |
| 2193 | c.1958C>A, p.Ser653Ter | LoF | Het | ER+/HER2- | 23 | — | — | Strong | 3 | Failed | |
| 2251 | c.2467C>T, p.Arg823Ter | LoF | Het | ER+/HER2- | 24 | — | MS | Strong | 3, 5 | na | |
| 1031 | c.3207delA, p.Asn1070IlefsTer6 | LoF | Het | ER+/HER2+ | 8 | — | MS | No | 25 | Failed | |
| 2923 | RAD51B | c.103C>T, p.Pro35Ser | MS | Het | TN | 32 | MS | — | na | na | na |
| 1932 | c.277G>A, p.Ala93Thr | MS | Het | TN | 2 | — | — | na | na | Failed | |
| 1795 | c.436G>A, p.Ala146Thr | MS | Mutant Loss | TN | 30 | LoF | — | na | na | na | |
| 3024 | c.553T>G, p.Cys185Gly | MS | Mutant Loss | TN | 76 | — | — | na | na | DNT | |
| 3054 | WRN | c.171C>A, p.Tyr57Ter | LoF | Het | ER+/HER2- | 24 | — | MS | Weak | 5 | Failed |
| 2963 | c.944_948delTAAAC, p.Leu315PhefsTer5 | LoF | Het | ER+/HER2- | 24 | — | — | Weak | 5 | Failed | |
| 1115 | c.3961C>T, p.Arg1321Ter | LoF | Het | ER+/HER2- | 40 | MS | MS | No | 5, 6 | Failed | |
| 1847 | c.4216C>T, p.Arg1406Ter | LoF | WT Loss | ER+/HER2- | 53 | — | MS | Strong | 3 | DNT | |
| 2562 | c.4216C>T, p.Arg1406Ter | LoF | Het | ER+/HER2- | 29 | — | — | Strong | 3, 11 | Failed | |
| 3093 | c.4216C>T, p.Arg1406Ter | LoF | WT Loss | ER+/HER2- | 5 | — | MS | na | na | na | |
| 1349 | c.4216C>T, p.Arg1406Ter | LoF | Het | TN | 43 | — | — | Strong | 3 | Failed | |
| 863 | XRCC2 | c.39 + 1G>A | LoF | Het | ER-/HER2+ | 12 | LoF | — | Strong | 3 | Failed |
| 3062 | c.794T>A, p.Leu265Ter | LoF | WT Loss | TN | 44 | LoF | — | Strong | 3 | DNT |
Subject 2727 also carried a germline ATM variant that had biallelic loss in tumor. Subject 3054 carried a germline RAD51C that had biallelic loss in tumor. Subject 3093 carried variants of interest in BLM and WRN. Subject 901 carried variants in both ERCC5 and FANCM. “—” 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.
WT loss, somatic loss of the wild-type 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.
Proportion of mutational signature 3 (COSMIC v2, assessed on whole-exome sequenced tumors only) above 25% is classified as “strong,” below 25% as “weak.”