Cancer demographics in the UAE
The UAE National Cancer Registry (UAE-NCR) published its first comprehensive cancer data in 2019 (2) with 4,299 newly diagnosed cancer cases, with 26.9% of cancers among the UAE nationals. Breast cancer has been UAE nationals' most common registered cancer in 2017, followed by colorectal and thyroid cancers (22). Here, we analysed 306 patients diagnosed with four cancers; Breast, Ovarian, Prostate, and Pancreatic (Fig. 1A) across 14 Arab nationalities, with 48% of the cases registered as UAE nationals (Emirati Cohort) and 76% as UAE and Arab nationalities (Table 1 & Suppl. Figure 1A).
Among the UAE nationals/Emirati cohort, 106 patients were diagnosed with Breast cancer (72%; median follow-up = 52 months), 19 with Ovarian cancer (13%; median follow-up = 31 months), 14 with Prostate cancer (9.5%; median follow up = 71 months) and 9 with Pancreatic cancer (6%; median follow up = 12 months).
Across all nationalities, the mean follow-up of patients in the four cancer types was 36.858 months ± 39.418 (n = 304) (Fig. 1B)
The Classification of breast cancer subtypes amongst patients of all nationalities, was done through immunohistochemical expression of hormone receptors: estrogen receptor positive (ER+), progesterone receptor positive (PR+), human epidermal growth factor receptor positive (HER2+), triple-positive (TP) and triple-negative (TNBC). The data revealed that 69% of the patients were ER/PR positive (161/233); 23% were HER2 positive (52/228); 18% were TNBC (44/240; 14 of these were UAE nationals/Emirati cohort) and 10% were TP (17/240) (Table 1).
Landscape of gBRCA1/2 variants in the UAE
Thirty-eight out of 306 cancer patients carried a germline BRCA1 or BRCA2 mutation (14 BRCA1 and 25 BRCA2) (Fig. 2), with the distribution of PV/LPVs summarised in Table 2. Among the 306 patients, 19 PVs/LPVs were identified in 23 patients (7.52%). The prevalence was similar among UAE nationals (7.43%) and non-UAE nationals (7.59%) and very similar to a recent study from the Bahraini population (23). Furthermore, the PV/LPVs were equally distributed among BRCA1 and BRCA2 genes. However, PV/LPVs were more prevalent in BRCA2 in patients with UAE nationality/Emirati cohort (4.7 vs. 2.7%). Furthermore, only one LPV was detected in a patient with UAE nationality. Based on the type of variation, eight were frameshift, six were nonsense, two were missense, and two were splice variants (Fig. 2). In addition, one large fragment insertion was found in a patient with UAE nationality/Emirati cohort. On the other hand, stratification by cancer subtype revealed 17 breast cancer patients harboring PV/LPVs (7.1%). Interestingly, PV/LPVs were more prevalent in BRCA2 than BRCA1 in breast cancer patients with UAE nationality/Emirati population (4.7% vs. 1.9%). PVs were detected in a slightly higher proportion in ovarian (12.5%) and prostate cancer patients (10.5%) while PVs in pancreatic cancer patients was not detected.
Table 2
BRCA1 and BRCA2 germline variants in cancer patient cohort. The HGVS nomenclature is based on BRCA1 transcript NM_007300.4 and for BRCA2 is NM_000059.3.
Case ID | PDX | Molecular Subtype | Nationality, Age, Gender | BMI at time of diagnosis | Family History | Gene | Exon # | HGVS variant nomenclature Chr location (hg38) | Predicted effect at Protein level | Mutation type | In silico software prediction | ACMG Classification ClinVar & dbSNP |
BSCP-192 | Breast Cancer | TNBC | India 43Y/F | 23.5 kg/m² | Yes | BRCA1 | Exon 2 | c.68_69delAG chr17: 43124028 | p.Glu23ValfsTer17 | Frameshift | NA | Pathogenic (PVS1 + PP5 + PM2) rs80357914 |
GB094-21 | Ovarian Cancer | NA | Yemen, 52Y/F | 31.24 kg/m² | NA | BRCA1 | Exon 10 | c.1140dup chr17:43094390 | p.(Lys381GlufsTer3) | Insertion Frameshift | NA | Pathogenic (PVS1 + PM2 + PP5) ClinVar ID: 231732 rs876659327 |
PHC-359 | Breast Cancer | PR | Egypt, 32Y/F | 25.33 kg/m² | NA | BRCA1 | Exon 10 | c.1224del chr17:43094307 | p.Val409Ter | Nonsense Stop-gained | NA | Pathogenic (PVS1 + PP5 + PM2) ClinVar: 252436 rs879255320 |
GB049-21 | Breast Cancer | TNBC | UAE, 44Y/F | 37.81 kg/m² | NA | BRCA1 | Exon 10 | c.3228_3229delAG chr17:43092302 | p.Gly1077AlafsTer8 | Deletion Frameshift | NA | Pathogenic (PVS1 + PP5 + PM2) ClinVar: 37516 rs80357635 |
GB061-22 | Breast Cancer | TNBC | UAE, 54Y/F | 30.78 kg/m² | Yes | BRCA1 | Exon 10 | c.4065_4068del chr17:43091463 | p.Asn1355LysfsTer10 | Deletion Frameshift | NA | Pathogenic (PVS1 + PP5 + PM1 + PM5 + PM2) ClinVar: 17674 rs80357508 |
BSCP-190 | Ovarian Cancer | NA | UAE, 71Y/F | 40.54 kg/m² | Yes | BRCA1 | Exon 10 | c.4065_4068del chr17:43091463 | p.Asn1355LysfsTer10 | Deletion Frameshift | NA | Pathogenic (PVS1 + PP5 + PM2) ClinVar ID: 17674 rs80357508 |
BSCP-274 | Ovarian Cancer | NA | UAE, 48Y/F | 26.0 kg/m² | Yes | BRCA1 | Exon 10 | c.4065_4068del chr17:43091463 | p.Asn1355LysfsTer10 | Deletion Frameshift | NA | Pathogenic (PVS1 + PP5 + PM2) ClinVar ID: 17674 rs80357508 |
GB013-22 | Breast Cancer | PR | Pakistan, 35Y/F | 26.14 kg/m² | NA | BRCA1 | Exon 11 | c.4183C > T chr17:41242963 | p.Gln1395Ter | Nonsense Stop-gained Splice region | NA | Pathogenic (PVS1 + PP5 + PM2) ClinVar: 55125 rs80357260 |
GB022-22 | Breast Cancer | ER/PR | Philippine, 35Y/F | 20.31 kg/m² | NA | BRCA1 | Exon 19 | c.5251C > T chr17:41209095 | p.Arg1751Ter | Nonsense Stop-gained | NA | Pathogenic (PP5 + PVS1 + PS3 + PM2) ClinVar: 55480 rs80357123 |
GB109-22 | Breast Cancer | ER/PR | UAE, 41Y/F | 35.34 kg/m² | No | BRCA2 | Exon 3 | c.262_263del chr13:32319269 | p.Leu88AlafsTer12 | Deletion Frameshift | NA | Pathogenic (PVS1 + PP5 + PM2) Clinvar: 51317 rs276174825 |
NRLP-197 | Breast Cancer | ER/PR | UAE, 51Y/F | 34.93 kg/m² | No | BRCA2 | Exon 3 | c.262_263del chr13:32319269 | p.Leu88AlafsTer12 | Deletion Frameshift | NA | Pathogenic (PVS1 + PP5 + PM2) ClinVar ID: 51317 rs276174825 |
DH-431 | Prostate Cancer | NA | Palestine, 62Y/M | 37.98 kg/m² | NA | BRCA2 | Exon 11 | c.2254_2257del chr13:32336606 | p.Asp752PhefsTer19 | Deletion Frameshift | NA | Pathogenic (PVS1 + PP5 + PM2) ClinVar ID: 51260 rs80359326 |
GB065-22 | Breast Cancer | TNBC | Sri Lanka 41Y/F | 27.11 kg/m² | No | BRCA2 | Exon 11 | c.4003G > T chr13:32338358 | p.Glu1335Ter | Nonsense Stop-gained | NA | Pathogenic (PVS1 + PM2) rs747070579 ClinVar: 233112 |
BSCP-272 | Breast Cancer | ER/PR | Pakistan, 54Y/M | 29.74 kg/m² | Yes | BRCA2 | Exon 11 | c.5222_5225del chr13:32339574 | p.Ser1741ThrfsTer35 | Deletion Frameshift | NA | Pathogenic (PM2 + PMS + PVS1) ClinVar ID: 126063 rs80359498 |
BSCP-328 | Breast Cancer | ER/PR | UAE, 33Y/F | 28.37 kg/m² | NA | BRCA2 | Exon 11 | c.5645C > A chr13:32340000 | p.Ser1882Ter | Nonsense Stop-gained | NA | Pathogenic (PVS1 + PP5 + PM2) ClinVar ID: 37984 rs80358785 |
GB140-21 | Breast Cancer | TNBC | UAE, 52Y/F | 33.95 kg/m² | NA | BRCA2 | Exon 13 | c.7006C > T chr13:32346895 | p.Arg2336Cys | Missense splice region | Sift: tolerated (1) PolyPhen: benign | Likely Pathogenic (PM2 + PMS + PVS1) ClinVar ID: 96845 rs431825347 |
BSCP-281 | Breast Cancer | ER/PR | Iraq, 52Y/F | 29.22 kg/m² | Yes | BRCA2 | Exon 13 | c.7007G > A chr13:32346896 | p.Arg2336His | Missense | Sift: damaging (0.4567) MutationTaster: disease causing (0.81) | Pathogenic (PP5 + PS3 + PM5+ PP3 + PM2) ClinVar ID: 38077 rs28897743 |
BSCP-345 | Prostate Cancer | NA | UAE, 72Y/M | 25.51 kg/m² | NA | BRCA2 | Exon 15 | c.7558C > T chr13:32356550 | p.Arg2520Ter | Nonsense Stop-gained | NA | Pathogenic (PVS1 + PP5 + PM2) ClinVar ID: 52353 rs80358981 |
BSCP-284 | Breast Cancer | ER/PR/HER2 | UAE, 58Y/F | 32.46 kg/m² | Yes | BRCA2 | Exon 16 | insertion of 1.8 Kb genomic sequence of ARL13A within exon 16 of BRCA2 chr13:32931928/chrX:100226563–100228377 (hg19) | p.? | Large insertion | NA | Pathogenic (PVS1 + PM2) |
BSCP-249 | Ovarian Cancer | NA | UAE, 47Y/F | 21.09 kg/m² | Yes | BRCA2 | Exon 18 | c.8023A > G chr13:32363225 | p.lle2675Val | Missense | Sift: Damaging (0.9125) MutationTaster: Disese causing (0.5239) | Pathogenic (PP5 + PS3 + PM2 + PP3 + BP1) ClinVar ID: 52475 rs397507954 |
BSCP-341 | Breast Cancer | ER/PR | Philippine, 40Y/F | 21.64 kg/m² | NA | BRCA1 | Exon 20 | c.5314C > T chr17:43057078 | p.Arg1772Ter | Nonsense Stop-gained | NA | Pathogenic (PVS1 + PP5 + PS3 + PM2) ClinVar: 55480 rs80357123 |
GB055-21 | Breast Cancer | ER/PR | India 40Y/F | 28.44 kg/m² | NA | BRCA2 | Exon 25 | c.9276T > G chr13:32394708 | p.Tyr3092Ter | Nonsense Stop-gained | NA | Pathogenic (PVS1 + PP5 + PM2 + PM3) ClinVar ID: 52803 rs80359197 |
BSCP-305 | Breast Cancer | ER/PR | Pakistan, 42Y/F | 28.95 kg/m² | NA | BRCA2 | Exon 25 | c.9435_9436del chr13:32394864 | p.Ser3147CysfsTer2 | Deletion Frameshift | NA | Pathogenic (PVS1 + PP5 + PM2) ClinVar ID: 38240 rs80359763 |
PDX: Primary diagnosis; TNBC: Triple negative breast cancer; BMI: body mass index |
The influence of gBRCA1/2 variants of uncertain significance (VUSs) on cancer risk and their association with the response to treatment is uncertain (24). In previous studies conducted on high-risk families, variants of uncertain significance exhibited a frequency of up to 15% for the BRCA genes (25). Assessing the pathogenicity of VUS of BRCA1/2 poses a real challenge where functional studies are needed further to delineate the impact of VUS on cellular function. The influence of BRCA1/2 VUSs on cancer risk and their association with the response to treatment is uncertain, and here we summarise the VUS findings across the two patient cohorts, intending to share such findings for further functional studies.
We identified 16 VUSs in 15 patients (4.9%) (Table 3). The prevalence of VUSs was slightly higher in patients of UAE nationality/Emirati cohort than in other nationalities (5.4 vs. 4.4%). The VUSs were more prevalent in BRCA2 than in BRCA1 (12 vs. 4). All the VUS were missense variants mostly occurring in exon 10 of BRCA1 (n = 3) and exon 11 of BRCA2 (n = 3) (Table 3). Stratification by cancer subtype revealed 13 breast cancer patients harbouring VUS (5.4%).
Table 3
List of Variant of Unknown Significance identified in Cancer Patient Cohort.
Case ID | PDX | Molecular Subtype | Nationality, Age, Gender | BMI | Family History | Gene | Exon | HGVS coding variant Chr location (hg38) | HGVS protein | Mutation Type | In silico software prediction | gnomAD Frequency (Total) % | ACMG Classification |
GB032-20 | Breast Cancer | ER/PR positive | UAE, 57Y/F | 29.59 kg/m² | No | BRCA2 | 11 | c.5474C > T chr13:32339829 | p.Ala1825Val | Missense | Sift: tolerated (0.04879) MutationTaster: Polymorphism (0.08975) REVEL: Benign (0.5838) | 0.0028 | VUS (PM2 + BP4) ClinVar ID: 37968 rs397507352 |
GB014-21 | Ovarian Cancer | NA | Sudan, 56Y/F | 20.31 kg/m² | No | BRCA2 | 11 | c.4574A > T chr13:32338929 | p.His1525Leu | Missense | Sift: deleterious (0.5646) PolyPhen: probably damaging REVEL: benign (0.7323) | 0 | VUS (PM2 + BP4) ClinVar ID: 838870 rs397507336 |
GB118-21 | Breast Cancer | ER positive | Philippine, 42Y/F | 23.42 kg/m² | No | BRCA2 | 10 | c.1826A > G chr13:32333304 | p.Gln609Arg | Missense | Sift: tolerated (0.1) Polyphen: benign REVEL: benign (0.5669) | 0.00066 | VUS (PM2) ClinVar ID: 51210 rs80358473 |
GB123-21 | Breast Cancer | ER positive | Algeria, 46Y/F | 23.53 kg/m² | No | BRCA2 | 22 | c.8782G > T chr13:32379344 | p.Ala2928Ser | Missense | Sift: deleterious (0.01) PolyPhen: probably damaging (0.96) REVEL: benign (0.4015) | 0.00066 | VUS (PM2 + PP3) ClinVar ID: 141459 rs587781762 |
GB002-22 | Breast Cancer | ER positive/ HER2 positive | Uganda, 43Y/F | 27.51 kg/m² | No | BRCA2 | 16 | c.7676C > G chr13:32357800 c.7712A > G chr13:32357836 | p.Ser2559Cys p.Glu2571Gly | Missense Missense | Sift: tolerated (0.5125) Polyphen: probably damaging REVEL: uncertain (0.8669) Sift: deleterious (0.7849) Polyphen: probably damaging REVEL: Pathogenic (0.9154) | 0.00066 0.0032 | VUS (PM2 + PP3) ClinVar ID: 409479 rs1060502421 VUS (PM2 + PP3) ClinVar: 52392 rs55689095 |
GB003-22 | Breast Cancer | ER positive | UAE, 66Y/F | 35.17 kg/m² | No | BRCA2 | 12 | c.6842G > A chr13:32344558 | p.Gly2281Glu | Missense – Splice region | Sift: deleterious PolyPhen: probably damaging (1) | 0.000408 | VUS (PM2 + PP3) ClinVar ID: 926077 rs80358908 |
BSCP-260 | Breast Cancer | ER/PR positive | UAE, 51Y/F | 26.31 kg/m² | Yes | BRCA1 | 10 | c.1250A > G chr17:43094281 | p.Asn417Ser | Missense | Sift: tolerated (0.4308) MutationTaster: uncertain (0.08975) REVEL: Pathogenic (0.9154) | 0 | VUS (PM2 + BP4) ClinVar ID: 54174 rs80357113 |
BSCP-304 | Breast Cancer | HER2 positive | UAE, 41Y/F | 25.48 kg/m² | No | BRCA1 | 20 | c.5260G > C chr17:43057069 | p.Glu1754Gln | Missense | Sift: pathogenic (0.9125) MutationTaster: disease casuing (0.81) REVEL: uncertain (0.8055) | 0.0036 | (VUS) (PM2 + PM1) ClinVar ID: 462666 rs80357432 |
BSCP-333 | Breast Cancer | ER/PR positive | India, 34Y/F | 31.6 kg/m² | Yes | BRCA2 | 18 | c.8117A > G chr13:32363319 | p.Asn2706Ser | Missense | Sift: benign (0.04417) MutationTaster: uncertain (0.08975) REVEL: benign (0.4129) | 0.0072 | VUS (PM2 + BP4) ClinVar ID: 38139 rs80359055 |
BSCP-347 | Breast Cancer | TNBC | UAE, 50Y/F | 29.64 kg/m² | No | BRCA2 | 18 | c.8117A > G chr13:32363319 | p.Asn2706Ser | Missense | Sift: benign (0.4339) MutationTaster: uncertain (0.08975) REVEL: benign (0.4129) | 0.0072 | VUS (PM2 + BP4) ClinVar ID: 38139 rs80359055 |
BSCP-350 | Breast Cancer | TNBC | India, 31Y/F | 24.86 kg/m² | No | BRCA1 BRCA2 | 10 3 | c.1593G > A chr17:43093938 c.147A > C chr13:32319156 | p. Met531Ile p. Glu49Asp | Missense Missense | Sift: benign (0.09543) MutationTaster: uncertain (0.08975) REVEL: uncertain (0.8043) Sift: benign (0.09543) MutationTaster: benign (0.2794) REVEL: benign (0.222) | 0 0.0004 | VUS (PM2 + BP4) VUS (PM2 + BP4) ClinVar ID: 920387 rs779648876 |
GB054-22 | Prosate Cancer | NA | UAE, 75Y/M | 37.34 kg/m² | Yes | BRCA1 | 10 | c.1771A > G chr17:43093760 | p.Ile591Val | Missense | Sift: tolerated (0.19) PolyPhen: possibly damaging (0.465) REVEL: uncertain (0.8407) | 0.0004 | VUS (PM2) ClinVar ID: 421781 rs1064795358 |
GB087-22 | Breast Cancer | ER positive | UAE, 63Y/F | 22.83 kg/m² | No | BRCA2 | 23 | c.9104A > C chr13:32379900 | p.Tyr3035Ser | Missense | Sift: deleterious PolyPhen: probably damaging (0.99) REVEL: uncertain (0.8787) | 0.0048 | VUS (PM2 + PP3) ClinVar ID: 38211 rs80359165 |
GB129-22 | Breast Cancer | ER/PR positive | UAE, 50Y/F | 41.87 kg/m² | No | BRCA2 | 11 | c.3762G > T chr13:32338117 | p.Glu1254Asp | Missense | Sift: tolerated (0.07) PolyPhen: benign (0.19) REVEl: benign (0.4811) | 0.00041 | VUS (PM2 + BP4) ClinVar ID: 231869 rs777028631 |
GB130-22 | Breast Cancer | ER/PR positive | Iran, 43Y/F | 27.73 kg/m² | No | BRCA2 | 16 | c.7628A > G chr13:32357752 | p.Tyr2543Cys | Missense | Sift: tolerated (0.17) PolyPhen: benign (0.055) REVEL: uncertain (0.8753) | 0.00319 | VUS (PM2 + BP1) ClinVar ID: 102758 rs431825354 |
Among 137 healthy individuals, five PVs were identified in 5 individuals (3.6%) (Table 4). Based on the variant type, three were deletions, and two were missense variants. All three deletion variants were detected in individuals with UAE nationality/Emirati cohort only. Compared to cancer cohort, a total of 4 VUS were detected in 9 healthy individuals (6.6%) (Table 5). All the VUS were missense variants. The most common VUS detected in four out of eight individuals with UAE nationality/Emirati cohort was observed to be rs80358256 (p.Asn886Ser), making this variant an exciting target for further functional research and for guiding personalized treatment options for the patients.
Table 4
List of Pathogenic and Likely Pathogenic variants in BRCA1/2 in Family screening cohort
Case ID | Nationality, Age, Gender | BMI at time of testing | Family History | Gene | Exon # | HGVS coding variant Chr location (hg38) | HGVS protein | Mutation type | In silico software prediction | ACMG Classification ClinVar & dbSNP |
GB071-20 | Bahrain, 42Y/F | 21.94 kg/m² | Yes | BRCA2 | 19 | c.8377G > A chr13:32370447 | p.Gly2793Arg | Missense | Sift: deleterious (0.9125) PolyPhen: Damaging (1.00) REVEL: Pathogenic (0.92) | Pathogenic (PP5 + PP3 + PM2 + BP1) ClinVar: 52569 rs80359082 |
GB063-21 | UAE, 45Y/F | 29.6 kg/m² | Yes | BRCA2 | 9 | c.771_775del chr13:32331004 | p.Asn257LysfsTer17 | Deletion | NA | Pathogenic (PVS1 + PP5 + PM2) ClinVar: 9326 rs80359671 |
GB023-22 | Sudan, 65Y/M | 24.21 kg/m² | Yes | BRCA1 | 17 | c.5095C > T chr17:43063931 | p.Arg1699Trp | Missense | Sift: deleterious PolyPhen: possibly damaging (0.885) REVEL: | Pathogenic (PS3 + PM1 + PP5 + PM5 + PP3 + PM2) ClinVar: 55396 rs55770810 |
BSCP-310 | UAE, 49Y/F | 34.71 kg/m² | Yes | BRCA1 | 10 | c.4065_4068del chr17:43091463 | p.Asn1355LysfsTer10 | Deletion | NA | Pathogenic (PVS1 + PP5 + PM2) ClinVar: 17674 rs80357508 |
GB082-22 | UAE, 44Y/F | 32.83 kg/m² | Yes | BRCA1 | 10 | c.3756_3759del chr17:43091772 | p.Ser1253ArgfsTer10 | Deletion | NA | Pathogenic (PVS1 + PM2 + PP5) ClinVar: 17673 rs80357868 |
Table 5
List of variant of unknown significance identified in Family Screening Cohort
Case ID | Nationality, Age, Gender | BMI at time of testing | Family History | Gene | Exon | HGVS coding variant Chr location (hg38) | HGVS protein | Mutation Type | In silico software prediction | gnomAD Frequency (Total) % | ACMG Classification |
GB079-21 | UAE, 29Y/F | 30.08 kg/m² | Yes | BRCA2 | 11 | c.2892A > T chr13:32337247 | p.Lys964Asn | Missense | Sift: tolerated (0.1) Polyphen: benign (0.355) REVEL: Benign (0.11) | 0.00443 | VUS/Likely Benign (BP4 + BP1 + PM2) ClinVar ID: 133728 rs587778119 |
GB098-21 | UAE, 47Y/F | 34.85 kg/m² | Yes | BRCA1 | 10 | c.1396C > G chr17:43094135 | p.Aly466Gly | Missense | Sift: tolerated (0.1) Polyphen: possibly damaging (0.355) REVEL: uncertain (0.478) | 0 | VUS (PM2) ClinVar ID: 54240 rs80356964 |
GB133-21 | UAE, 37Y/F | 20.08 kg/m² | Yes | BRCA2 | 11 | c.2892A > T chr13:32337247 | p.Lys964Asn | Missense | Sift: tolerated (0.1) Polyphen: possibly damaging (0.355) REVEL: Benign (0.11) | 0.00443 | VUS (PM2 + BP4) ClinVar ID: 133728 rs587778119 |
GB137-21 | Jordan, 47Y/F | 43.43 kg/m² | Yes | BRCA2 | 10 | c.1472C > G chr13:32332950 | p.Thr491Ser | Missense | Sift tolerated (0.1) Polyphen benign (0.355) REVEL: Benign (0.2570) | 0.00042 | VUS (PM2 + BP4) ClinVar ID: 37742 rs397507268 |
NRLP-222 | UAE, 44Y/F | 25.76 kg/m² | Yes | BRCA2 | 11 | c.2892A > T chr13:32337247 | p.Lys964Asn | Missense | Sift: tolerated (0.1) Polyphen: possibly damaging (0.355) REVEL: Benign (0.11) | 0.00443 | VUS (PM2 + BP4) ClinVar ID: 133728 rs587778119 |
GB077-22 | UAE, 21Y/F | 24.56 kg/m² | Yes | BRCA2 | 11 | c.2657A > G chr13:32337012 | p.Asn886Ser | Missense | Sift: tolerated (0.36) PolyPhen: probably damaging (0.985) REVEL: benign (0.068) | 0.00043 | VUS (PM2 + BP4) Clinvar:91782 rs80358526 |
GB091_22 | UAE, 24Y/F | 25.02 kg/m² | Yes | BRCA2 | 11 | c.2657A > G chr13:32337012 | p.Asn886Ser | Missense | Sift: tolerated (0.36) PolyPhen: probably damaging (0.985) REVEL: benign (0.068) | 0.00043 | VUS (PM2 + BP4) rs80358526 ClinVar ID: 91782 |
GB092_22 | UAE, 17Y/F | 29.69 kg/m² | Yes | BRCA2 | 11 | c.2657A > G chr13:32337012 | p.Asn886Ser | Missense | Sift: tolerated (0.36) PolyPhen: probably damaging (0.985) REVEL: benign (0.068) | 0.00043 | VUS (PM2 + BP4) rs80358526 ClinVar ID: 91782 |
GB094-22 | UAE, 25Y/F | ND | Yes | BRCA2 | 11 | c.2657A > G chr13:32337012 | p.Asn886Ser | Missense | Sift: tolerated (0.36) PolyPhen: probably damaging (0.985) REVEL: benign (0.068) | 0.00043 | VUS (PM2 + BP4) rs80358526 ClinVar ID: 91782 |
gBRCA1/2 variants and breast cancer subtypes
Stratification by breast cancer subtypes showed that the majority of patients were ER/PR positive (69%) (n = 161) (Table 1). Out of these 161, fifteen were BRCA variant carriers (Tables 2–3). Among these carriers, PVs were detected in 66.6% of patients. After BRCA, the dominant subtype observed in breast cancer patients was was HER2 subtype (23%). On the other hand, two patients were found to be PR positive while five were ER positive. With respect to VUS, Only two patients (one with BRCA1 mutation and the other with BRCA2 mutation) were observed to be carrying VUS. While PVs were detected in PR-positive patients in BRCA1, VUSs were detected in ER-positive patients in BRCA2.The Triple negative breast cancer (TNBC) was observed in 18% of the patients (n = 44) while 7% (n = 17) of the patients were observed to be triple-positive (TP). In 7 out of 44 TNBC patients (15.9%), BRCA variants were observed While PVs/NPVs were detected in five of the TNBC patients (3 BRCA1, 2 BRCA2). In addition, VUS was detected in two TNBC patients (1 BRCA2, 1 BRCA1/BRCA2). In triple positive (TP) patients, only one patient was observed to be BRCA positive (BRCA2) carrying a PV.
Impact of BRCA1/2 variants on cancer risk
We did not observe any association between BRCA1/2 variants and cancer risk (OR = 1.26, CI = 0.67–2.37, P = 0.471). Similarly, In breast cancer (OR = 1.25, CI = 0.65–2.40, P = 0.508), ovarian cancer (OR = 1.56, CI = 0.52–4.68, P = 0.424), and prostate cancer (OR = 2.17, CI = 0.64–7.39, P = 0.126), no statistical association was observed. In pancreatic cancer, BRCA1/2 variants were not detected.
Impact of Body Mass Index (BMI) on cancer risk
In our study, we did not observe any significant difference in the distribution of BMI between cases and controls (28.7 vs. 27.9 kg/m2, P = 0.180). Furthermore, a similar trend was observed upon stratified analysis by cancer subtype (breast cancer: 28.9 vs. 27.9 kg/m2, P = 0.140; ovarian cancer: 29.1 vs. 27.9 kg/m2, P = 0.394, pancreatic cancer: 28.3 vs. 27.9 kg/m2, P = 0.805; prostate cancer: 27.6 vs. 27.9 kg/m2, P = 0.852). Lastly, we found no association between BMI and cancer among BRCA1/2 carriers (P = 0.688).