Lynch syndrome (LS) is the most common cause of hereditary colorectal cancers (CRC) and is associated with an increased risk for ovarian and endometrial cancers. There is lack of knowledge on the epidemiology of LS in the non-Caucasian populations especially in Qatar. The aim of this retrospective study is to explore the prevalence of LS in a selected high-risk cohort in the State of Qatar in addition to investigating the frequency and genotype-phenotype correlation associated with mismatch repair genes pathogenic variants. Retrospective review of medical records of 31 individuals with LS, 20 affected with colorectal cancer and 11 unaffected with family history of cancers, referred from January 2017 until August 2020. The prevalence of LS among affected and unaffected patients is 22% (20/92) and 2.2% respectively. Among affected individuals, MLH1 and MSH2 genes were highly frequent while for unaffected individuals, a recurrent PMS2 pathogenic variant was reported in several related individuals suggesting a tribal effect. This study highlights the epidemiology of LS in high-risk cohort in Qatar which helps to provide recommendations on genetic testing, and personalize surveillance and management programs

Background: Hereditary breast and ovarian cancer is an inherited condition caused by pathogenic (P) or likely pathogenic (LP) variants in the BRCA1 and BRCA2 genes. Population-level sequencing allows for the identification of asymptomatic genotype-positive participants (GPPs) before disease onset. This study assessed the feasibility and impact of returning clinically relevant BRCA results to participants at the Qatar Precision Health Institute (QPHI). Methods: We established a structured framework to identify and refer asymptomatic individuals who were found to carry P/LP variants in BRCA among 6142 QPHI participants. The process integrated genomic analysis, participant recontact, counseling, referral, variants validation, and personalized risk-reducing strategies. Results: Six variants (four BRCA1, two BRCA2) were validated in ten GPPs with a median age of 48 years (IQR: 40.5–56). Eight variants were confirmed through Sanger sequencing in a CAP-accredited laboratory at Hamad Medical Corporation. All eligible participants were referred for counseling and personalized clinical management. Four men initiated breast and prostate cancer surveillance, while four women pursued breast and ovarian surveillance. One asymptomatic GPP underwent prophylactic salpingo-oophorectomy, revealing early-stage ovarian cancer. Cascade testing identified 20 additional GPPs and, in one asymptomatic relative, facilitated the detection of early-stage uterine cancer. The genetic testing acceptability rate was 0.77 (95% CI: 0.46–0.94), with a 100% adherence to surveillance at 12- and 24-month follow-ups. Conclusions: This pilot demonstrates the feasibility and clinical utility of returning actionable BRCA1/2 findings and represents the first initiative in an Arabic population to implement the return of medically actionable BRCA results from a population-based biobank.

Background: Hereditary breast and ovarian cancer syndrome (HBOC) is the most common cause of hereditary breast and ovarian cancers in Qatar and worldwide, which is caused by pathogenic variants in the BRCA1 and BRCA2 genes. The aim of this retrospective study is to describe a common recurrent pathogenic variant in the BRCA1 gene that was observed in the native Qatari population with unique genotype–phenotype correlations. Methods: Medical records of Qatari patients (affected and unaffected) with personal and/or family history of breast and ovarian cancers who carry pathogenic/likely pathogenic variants in the BRCA1 gene were reviewed between 2013 and 2020. Epidemiological information and clinical data were reviewed, including age, gender, ethnic background, personal history of cancer, tumour characteristics, and family history. We used frequencies and proportions to describe the data and used Kaplan–Meier curves and log‐rank analysis to compare survival rates. For the analysis, we used Stata Corp. 2015. Stata Statistical Software: Release 14, College Station, TX: Stata Corp. LP. Ethical Compliance: Ethical committee approval was obtained from Hamad Medical Corporation IRB committee (MRC‐01‐20‐1086). Result: Sixty‐three Qatari affected patients and unaffected individuals who carry the BRCA1 variant were included in the study. Our result confirms the presence of a common recurrent pathogenic variant c.4787C>A p.(Ser1596Ter) among Qatari patients who belong to 8 consanguineous large families, followed by c.4065_4068del p.Asn1355fs, both in BRCA1 . The BRCA1 c.4787C>A variant is highly associated with early onset breast cancer, specifically invasive ductal carcinoma (IDC) triple negative breast cancer (stage I, grade III), rather than ovarian cancer. Additionally, the c.4787C>A variant was found to exhibit high penetrance in families with early‐onset breast cancer. Conclusion: We showed that BRCA1 c.4787C>A pathogenic variant is a highly recurrent variant among Qatari consanguineous families and contributes to the early onset breast cancer in Qatar. Early identification of this variant can aid in improving patients' survival and guide early personalized treatment and prevention.