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Author(s): Fizza Akbar[sup.1], Zahraa Siddiqui[sup.2], Muhammad Talha Waheed[sup.2], Lubaina Ehsan[sup.2,3], Syed Ibaad Ali[sup.3], Hajra Wiquar[sup.1], Azmina Tajuddin Valimohammed[sup.4], Shaista Khan[sup.5], Lubna Vohra[sup.5], Sana Zeeshan[sup.5], Yasmin Rashid[sup.4], Munira Moosajee[sup.4], Adnan Abdul [...], Background Breast cancer is the most common malignancy in women, affecting over 1.5 million women every year, which accounts for the highest number of cancer-related deaths in women globally. Hereditary breast cancer (HBC), an important subset of breast cancer, accounts for 5-10% of total cases. However, in Low Middle-Income Countries (LMICs), the population-specific risk of HBC in different ethnicities and the correlation with certain clinical characteristics remain unexplored. Methods Retrospective chart review of patients who visited the HBC clinic and proceeded with multi-gene panel testing from May 2017 to April 2020. Descriptive and inferential statistics were used to analyze clinical characteristics of patients. Fisher's exact, Pearson's chi-squared tests and Logistic regression analysis were used for categorical variables and Wilcoxon rank-sum test were used for quantitative variables. For comparison between two independent groups, Mann-Whitney test was performed. Results were considered significant at a p value of < 0.05. Results Out of 273 patients, 22% tested positive, 37% had a VUS and 41% had a negative genetic test result. Fifty-five percent of the positive patients had pathogenic variants in either BRCA1 or BRCA2, while the remaining positive results were attributed to other genes. Patients with a positive result had a younger age at diagnosis compared to those having a VUS and a negative result; median age 37.5 years, IQR (Interquartile range) (31.5-48). Additionally, patients with triple negative breast cancer (TNBC) were almost 3 times more likely to have a positive result (OR = 2.79, CI = 1.42-5.48 p = 0.003). Of all patients with positive results, 25% of patients had a negative family history of breast and/or related cancers. Conclusions In our HBC clinic, we observed that our rate of positive results is comparable, yet at the higher end of the range which is reported in other populations. The importance of expanded, multi-gene panel testing is highlighted by the fact that almost half of the patients had pathogenic or likely pathogenic variants in genes other than BRCA1/2, and that our test positivity rate would have only been 12.8% if only BRCA1/2 testing was done. As the database expands and protocol-driven referrals are made across the country, our insight about the genetic architecture of HBC in our population will continue to increase. Keywords: Hereditary breast Cancer, Germline pathogenic variant, Consensus guidelines, Genetic counseling, Genetic testing, Genetic services manuscript

Author(s): Nina Stramsvik[sup.1,2], Pernilla Olsson[sup.3], Berit Gravdehaug[sup.4], Hilde Lurås[sup.5,6], Ellen Schlichting[sup.7], Kjersti Jargensen[sup.8], Teresia Wangensteen[sup.8], Tone Vamre[sup.8], Cecilie Heramb[sup.8], Lovise Maehle[sup.8] and Eli Marie Grindedal[sup.8] Background Women with inherited pathogenic [...], Background In South-Eastern Norway, genetic testing for BRCA1 and BRCA2 is offered to breast cancer patients by their treating surgeon or oncologist. Genetic counselling from a geneticist or a genetic counsellor is offered only to those who test positive for a pathogenic variant or have a family history of cancer. This practice is termed 'mainstreamed genetic testing'. The aim of this study was to learn about patients' experience of this healthcare service. Methods Qualitative in-depth interviews were conducted with 22 breast cancer patients who had been diagnosed during the first half of 2016 or 2017 at one regional and one university hospital and who had been offered testing by their treating physician. A six-phase thematic approach was used to analyse the data. Results The participants had varied experiences of how and when testing was offered. Three main themes emerged from the analysis: 1. informational and communicational needs and challenges during a chaotic time, 2. the value of genetic testing and 3. the importance of standardised routines for mainstreamed genetic testing. Conclusions Despite the shock of their diagnosis and the varying experiences they had in respect of how and when testing was offered, all of the participants emphasised that genetic testing had been an important part of their diagnosis and treatment. Our results indicate that there is a need for continuous collaboration between geneticists, surgeons, oncologists and laboratory specialists in order to establish simple and robust routines so as to ensure that all eligible breast cancer patients are offered testing at a point when the test result can have an impact on treatment. Keywords: Breast cancer, BRCA1, BRCA2, Mainstreamed genetic testing, Qualitative study, Genetic testing for breast cancer

Author(s): Jessica Omark[sup.1,2], Eduardo Vilar[sup.3], Y Nancy You[sup.4], Leslie Dunnington[sup.1,5], Sarah Noblin[sup.1,6,7], Blair Stevens[sup.1,6] and Maureen Mork[sup.1,8] Background Lynch syndrome (LS) is a hereditary cancer syndrome affecting as many as [...], Background Individuals who have colorectal or endometrial cancers displaying loss of immunohistochemical staining of one or more mismatch repair proteins without an identifiable causative germline pathogenic variant have unexplained mismatch repair deficiency (UMMRD). Comprehensive germline genetic testing for Lynch syndrome (LS) includes sequencing and deletion/duplication analysis of MLH1, MSH2, MSH6, and PMS2, deletion analysis of EPCAM, and MSH2 inversion analysis. Updated genetic testing to include elements of comprehensive LS testing not previously completed could further clarify LS status in individuals with UMMRD, allowing for tailored screening guidelines for affected individuals and their family members. However, patient understanding of the potential impact of updated genetic testing for LS is unclear. This study aimed to evaluate the interest in and perceived impact of updated genetic testing among individuals with UMMRD at a tertiary academic center. Methods A survey evaluating interest in and perceived impact of updated genetic testing was mailed to 98 potential participants. Electronic health record review was completed for all individuals meeting eligibility criteria. Thirty-one individuals responded to the survey. Results Results indicate this population is highly interested in updated genetic testing with the perceived impact being primarily for family members to have appropriate genetic testing and screening. Electronic health record review indicates that clinicians have an evolving understanding of causes of UMMRD, representing a potential change in assessment of cancer risk. Conclusions Updated risk assessment and genetic counseling with a discussion of the benefits and limitations of germline and somatic genetic testing, is essential as the understanding of UMMRD and genetic testing recommendations for this population evolve. Keywords: Cancer, Genetic counseling, Genetic testing, Lynch syndrome, Mismatch repair deficiency, Oncology, Psychosocial impacts of genetic testing, Unexplained mismatch repair deficiency, Updated genetic testing

Given the importance of Africa to studies of human origins and disease susceptibility, detailed characterization of African genetic diversity is needed. The African Genome Variation Project provides a resource with [...]