Expanding the Genomic Landscape of HBOC and Cancer Risk Among Mutation Carriers
Abstract
1. Background
2. Results
2.1. Mutation Rate and Affected Genes
2.2. In Silico Analysis
2.3. Clinical Features of Patients and Families
3. Discussion
4. Materials and Methods
4.1. Patients
4.2. Genetic Testing
4.3. In Silico Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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ID | Sex (M/F) | Age at Testing | Clinical Phenotype and Age at Diagnosis | Mutation Type Gene/Name and dbSNP ID | Mutation in Other Genes | Family History | Number of Family Members Tested |
---|---|---|---|---|---|---|---|
Patient 1 | F | 44 | OC 44 | BRCA1: c.116G>A (p.Cys39Tyr) rs80357498 | - | Mother with PaC (42) | - |
Patient 2 | F | 74 | BC 73 | BRCA1: c.547+2T>A rs80358047 | - | Mother with OC (49) and sister with LC (65) | 4 |
Patient 3 | F | 55 | BC (54) and Melanoma (50) | BRCA1: c.4964_4982del (p.Ser1655Tyrfs*16) rs80359876 | MUTYH: c.1103G>A (p.Gly368Asp) rs36053993 | Two sisters with BC (35–46) | 2 |
Patient 4 | F | 63 | CRC 61 | BRCA1: c.3756_3759del (p.Ser1253Argfs*10) rs80359876 | - | Sisters with BC (45–46) and CRC (67), brother with CRC (71), and mother with BC (84) and OC (63) | 1 |
Patient 5 | F | 19 | BC 42 | BRCA1: c.5266dup (p.Gln1756Profs*74) rs80357906 | - | Mother with BC (60) and maternal grandmother with OC (62) and BC (63) | 3 |
Patient 6 | F | 65 | BC 65 | BRCA1: c.5266dup (p.Gln1756Profs*74) rs80357906 | - | Father with PC (55) | 1 |
Patient 7 | F | 49 | BC 49 | BRCA1: c.5266dup (p.Gln1756Profs*74) rs80357906 | - | Mother with CRC (65), sister with BC (42), and niece with BC (35) | 3 |
Patient 8 | F | 18 | LC 18 | BRCA1: c.5266dup (p.Gln1756Profs*74) rs80357906 | - | Mother with LC (48) and maternal grandmother with BC (65) | 1 |
Patient 9 | F | 50 | BC 46 | BRCA1: c.5266dup (p.Gln1756Profs*74) rs80357906 | - | Paternal aunt with CRC (69) and cousin with BC (46) | 1 |
Patient 10 | F | 54 | BC 54 | BRCA1: c.5266dup (p.Gln1756Profs*74) rs80357906 | - | Maternal cousin with BC (58) | 1 |
Patient 11 | F | 48 | BC 47 | BRCA1: c.5319dup (p.Asn1774Glnfs*56) rs80357823 | - | Maternal aunts with BC (57–67) | 1 |
Patient 12 | F | 53 | OC 52 | BRCA2: c.7558C>T (p.Arg2520*) rs80357823 | - | Sister with BC (50) and maternal grandmother with CRC (70) | - |
Patient 13 | M | 40 | PC 40 | BRCA2: c.8168A>G (p.Asp2723Gly) rs41293513 | - | Father with PC (65) | 3 |
Patient 14 | F | 39 | BC 37 | BRCA2: c.6037A>T (p.Lys2013*) rs80358840 | - | Father with CRC (61) and paternal aunts with BC (66) and LC (60) | 1 |
Patient 15 | F | 64 | BC 64 | BRCA2: c.67+1G>A rs81002796 | - | Father with LC (84) and paternal aunts with BC (75-35-30) | - |
Patient 16 | M | 59 | BC 59 | BRCA2: c.67+1G>A rs81002796 | - | Father with lymphoma (74) and sister with BC (42) | - |
Patient 17 | F | 58 | BC 58 | BRCA2: c.67+1G>A rs81002796 | - | Mother with BBC (80) | 4 |
Patient 18 | M | 65 | GC 63 | BRCA2: c.6486_6489del (p.Lys2162Argfs*5) rs80359598 | - | Mother with melanoma (68) and brother with GC (62) | 2 |
Patient 19 | F | 53 | BC 53 | BRCA2: c.6486_6489del (p.Lys2162Argfs*5) rs80359598 | - | Mother with BC (50) and OC (66) | - |
Patient 20 | M | 54 | BC 47 | BRCA2: c.6486_6489del (p.Lys2162Argfs*5) rs80359598 | - | Father with RCC (75) and sister with BC (47) | 5 |
Patient 21 | M | 63 | GC 63 | BRCA2: c.6468_6469del (p.Gln2157Argfs*18) rs80359596 | - | Mother with BC (70) and CRC (91) | - |
Patient 22 | F | 51 | BC 49 | BRCA2: c.6468_6469del (p.Gln2157Argfs*18) rs80359596 | - | Mother with BC (58) and maternal aunt with BC (69) | 1 |
Patient 23 | F | 43 | BC 39 | BRCA2: c.6405_6409del (p.Asn2135Lysfs*3) rs80359584 | - | Father with PC (63) and paternal uncles with PC (80) and CRC (81) | 2 |
Patient 24 | F | 48 | PC 48 | BRCA2: c.5073dup (p.Trp1692fs*3) rs80359479 | - | Maternal uncles with PC (70–78) and brothers with PaC (52) and PC (55) | 1 |
Patient 25 | F | 89 | BC 87 | BRCA2: c.3458dup (p.Thr1154Aspfs*4) rs80359386 | - | Mother with BC (70) | 3 |
ID | Sex (M/F) | Age at Testing | Clinical Phenotype and Age at Diagnosis | Mutation Type Gene/Name and dbSNP ID | Mutation in Other Genes | Family History | Number of Family Members Tested |
---|---|---|---|---|---|---|---|
Patient 1 | F | 49 | BC 49 | ATM: c.3802del (p.Glu1267_Val1268ins*) rs587779834 | - | Father with PC (66) and paternal aunts with PC (78) and CRC (36–85) | 2 |
Patient 2 | F | 60 | OC 60 | ATM: c.3802del (p.Glu1267_Val1268ins*) rs587779834 | - | Maternal aunt with BC (76) and sisters with BC (25–51), OC (37) and GC (47) | 1 |
Patient 3 | F | 46 | BC 46 | ATM: c.2548G>T (p.Glu850*) rs587782280 | - | Mother with BBC (50) and maternal aunts with BC (35–50) and PaC (57) | - |
Patient 4 | F | 54 | BC 53 | ATM: c.8833_8834del (p.Leu2945Valfs*10) rs786203030 | - | Mother with BC (82) and maternal aunts with BC (65-47-64) | 2 |
Patient 5 | F | 53 | OC 52 | ATM: c.2250G>A (p.Lys750=) rs1137887 | - | Maternal aunts with BC (80), LC (72) and sisters with LC (49) and BC (40) | 1 |
Patient 6 | F | 45 | BC 44 | ATM: delEX62_EX63 (Amirifar et al., 2021) [15] | - | Paternal aunts with RCC (79), BC (65), and GC (65–67) | - |
Patient 7 | F | 51 | BC 47, TC 47, OC 45 | CHEK2: c.920dup (p.Glu308Argfs*4) rs786203053 | - | Maternal grandmother with BC (75) and sister with BC (47) | - |
Patient 8 | F | 67 | Melanoma 67 | CHEK2: c.1427C>T (p.Thr476Met) rs142763740 | - | Brother with CRC (47) and son with RCC (42) | 2 |
Patient 9 | F | 30 | BC 30 | CHEK2: c.1427C>T (p.Thr476Met) rs142763740 | - | Mother with BC (63), maternal grandmother with BC (65), and maternal grandfather with PC (79) | - |
Patient 10 | F | 54 | BC 54 | CHEK2: c.1100del (p.Thr367fs*15) rs555607708 | - | Maternal aunts with LC (70–75), CRC (85–88), TC (77), and PaC (77) | 3 |
Patient 11 | M | 78 | CRC 77 | CHEK2: c.688G>A (p.Ala230Thr) rs748636216 | - | Maternal cousin with BC (60) and daughter with OC (42) | 1 |
Patient 12 | F | 52 | BBC 47 | CHEK2: c.470T>C (p.Ile157Thr) rs17879961 | MUTYH: c.536A>G (p.Tyr179Cys) rs34612342 | Mother with PaC (68) | 1 |
Patient 13 | M | 59 | CRC 57 | CHEK2: c.470T>C (p.Ile157Thr) rs17879961 | - | Father with GC (80) and paternal aunts with PC (78) and LC (66) | - |
Patient 14 | M | 81 | BC 81 | BRIP1: c.478del (p.Arg160Glufs*5) rs1555616150 | - | Paternal aunts with BC (50-54-60) | 3 |
Patient 15 | F | 73 | OC 72 | BRIP1: c.440dup (p.Tyr147*) rs786203521 | - | Maternal cousin with BC (50) | 1 |
Patient 16 | F | 49 | BC 37 | BRIP1: c.55dup (p.Tyr19Leufs*2) rs1567878148 | - | Mother with OC (70), maternal grandmother with CRC (72), and daughter with BC (49) | 1 |
Patient 17 | F | 55 | BC 55 | BRIP1: c.55dup (p.Tyr19Leufs*2) rs1567878148 | MUTYH: c.1187G>A (p.Gly396Asp) rs36053993 | Father with LC (63) and paternal cousin with BC (38) | 2 |
Patient 18 | F | 34 | BC 30 | PALB2: c.1919C>A (p.S640*) rs760094988 | - | Maternal grandmother with BC (81) | - |
Patient 19 | F | 39 | BC 29 | PALB2: c.1285_1286delAinsTC (p.I429SfsX12) (Vietri et al., 2015) [16] | - | Father with BC (70) and sisters with BC (32–40) | - |
Patient 20 | F | 67 | BC 43 | PALB2: c.2257C>T (p.Arg753*) rs180177110 | - | Mother with BC (60) and sister with lymphoma (39) | 2 |
Patient 21 | F | 57 | OC (43), BC (50), TC (50), LC (51) | PALB2: c.2161_2186dup (p.Ile730fs*11) rs1567217908 | - | Maternal aunt OC (60) | 1 |
Patient 22 | F | 46 | OC 46 | RAD51C: c.414G>C (p.Leu138Phe) rs267606999 | - | Mother with OC (52) and maternal aunt with GC (72) | 1 |
Patient 23 | F | 61 | PaC 61 | BARD1: c.539_540del (p.Tyr180*) rs779427628 | - | Mother with PaC (69) and maternal aunt with GC (82) | 3 |
Patient 24 | M | 76 | LC 63 | BARD1: c.1216C>T (p.Arg406*) rs377153250 | - | Sister with BC (50) and maternal aunts with PaC (78) | - |
Patient 25 | F | 69 | BC 52 | *CDH1: c.1678_1688del (p.Thr560Profs*24) novel | - | Father with GC (39) and sister with BC (73) and TC (50) | 1 |
Patient 26 | M | 44 | GC 70 | CDH1: c.2295+1G>C rs1596971108 | - | Maternal aunt with RCC (55) and one aunt with unspecified neoplasm | 2 |
Patient 27 | F | 25 | BC 25 | TP53: c.1009C>T (p.Arg337Cys) rs138398778 | - | Mother with BBC (30), maternal grandmother with BBC (30), and maternal grandfather with LC (76) | - |
Patient 28 | M | 35 | PC 35 | TP53: c.844C>T (p.Arg282Trp) rs28934574 | - | Mother with BC (46) | 2 |
Patient 29 | F | 40 | BC 37 | TP53: c.817C>T (p.Arg273Cys) rs121913343 | - | Maternal grandmother with BC (48) | 1 |
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Vietri, M.T.; Della Pepa, C.; Caliendo, G.; Mignano, A.; Albanese, L.; Zitiello, M.; Stilo, M.; Molinari, A.M. Expanding the Genomic Landscape of HBOC and Cancer Risk Among Mutation Carriers. Int. J. Mol. Sci. 2025, 26, 5928. https://doi.org/10.3390/ijms26135928
Vietri MT, Della Pepa C, Caliendo G, Mignano A, Albanese L, Zitiello M, Stilo M, Molinari AM. Expanding the Genomic Landscape of HBOC and Cancer Risk Among Mutation Carriers. International Journal of Molecular Sciences. 2025; 26(13):5928. https://doi.org/10.3390/ijms26135928
Chicago/Turabian StyleVietri, Maria Teresa, Chiara Della Pepa, Gemma Caliendo, Alessia Mignano, Luisa Albanese, Marialaura Zitiello, Marianna Stilo, and Anna Maria Molinari. 2025. "Expanding the Genomic Landscape of HBOC and Cancer Risk Among Mutation Carriers" International Journal of Molecular Sciences 26, no. 13: 5928. https://doi.org/10.3390/ijms26135928
APA StyleVietri, M. T., Della Pepa, C., Caliendo, G., Mignano, A., Albanese, L., Zitiello, M., Stilo, M., & Molinari, A. M. (2025). Expanding the Genomic Landscape of HBOC and Cancer Risk Among Mutation Carriers. International Journal of Molecular Sciences, 26(13), 5928. https://doi.org/10.3390/ijms26135928