Retesting of women who are negative for aBRCA1andBRCA2mutation using a 20-gene panel

Abstract

BackgroundThe value of retesting women who previously tested negative for a pathogenic variant (mutation) in BRCA1 and BRCA2 using an expanded panel of breast and ovarian cancer genes is unclear.MethodsWe studied 110 BRCA1/2-negative women who were retested using a panel of 20 breast and/or ovarian cancer susceptibility genes at the Advanced Molecular Diagnostics Laboratory (AMDL) at Mount Sinai Hospital in Toronto between March 2017 and March 2019. All patients had previously tested negative for BRCA pathogenic variants at the AMDL between January 2012 and March 2018 and were subsequently referred for retesting by their physician.ResultsOverall, six pathogenic variants in genes other than BRCA1 and BRCA2 were found (prevalence 5.5%). There were two pathogenic variants found in RAD51C, and one found in each of BRIP1, PALB2, PMS2 and PTEN. The prevalence of pathogenic variants was 6.5% for women affected with cancer (6 of 93), including 4.9% for women with breast cancer (4 of 82) and 22.2% for women with ovarian cancer (2 of 9). None of the 17 unaffected women had a clinically significant or pathogenic variant. There were 44 women (40%) for whom the result of the panel test was inconclusive due to the detection of a variant of uncertain significance.ConclusionsOur findings indicate that the retesting of BRCA1/2-negative individuals with an expanded panel of 20 breast and ovarian cancer genes can produce clinically relevant results, with a yield of 5.5% for pathogenic variants in genes other than BRCA1 and BRCA2.

Using Co-segregation and Loss of Heterozygosity Analysis to Define the Pathogenicity of Unclassified Variants in Hereditary Breast Cancer Patients

“…The frequency of pathogenic germline variants in patients who previously tested negative for pathogenic variants in BRCA1/BRCA2 was 3.8%. Although it is quite difficult to compare mutation frequencies among studies, due to differences in inclusion criteria and/or ethnicity, our mutation frequency corroborates other studies based on family cancer history inclusion criteria (25)(26)(27)(28)(29)(30)(31)(32).…”

Beyond BRCA1/2: Homologous Recombination Repair Genetic Profile in a Large Cohort of Apulian Ovarian Cancers

“…As far as concerns non- BRCA genes, we detected a deleterious mutation in 5.8% of our cohort patients (2.9% in BRIP1 , 1.5% each in BARD1 and RAD51C ), which is widely consistent with previous literature [ 21 , 23 , 24 ]. Pathogenic variants in BRIP1 , BARD1 , and RAD51C are all acknowledged as being associated with an increased risk of OC [ 22 , 26 , 27 ].…”

Criterios para la identificación de síndromes de cáncer de mama hereditarios. Revisión de la literatura y recomendaciones para el Instituto Nacional de Cancerología - Colombia

“…De los 41 artículos seleccionados, 8 no reportan la prevalencia de mutaciones específicamente en genes BRCA, ya sea porque se enfocaron en pacientes BRCA1-y BRCA2-negativos para evaluar otros genes de riesgo o porque no discriminaron los resultados por gen mutado (9)(10)(11)(12)(13)(14)(15)(16).…”