Genetic variants of prospectively demonstrated phenocopies in BRCA1/2 kindreds

Abstract

BackgroundIn kindreds carrying path_BRCA1/2 variants, some women in these families will develop cancer despite testing negative for the family’s pathogenic variant. These families may have additional genetic variants, which not only may increase the susceptibility of the families’ path_BRCA1/2, but also be capable of causing cancer in the absence of the path_BRCA1/2 variants. We aimed to identify novel genetic variants in prospectively detected breast cancer (BC) or gynecological cancer cases tested negative for their families’ pathogenic BRCA1/2 variant (path_BRCA1 or path_BRCA2).MethodsWomen with BC or gynecological cancer who had tested negative for path_BRCA1 or path_BRCA2 variants were included. Forty-four cancer susceptibility genes were screened for genetic variation through a targeted amplicon-based sequencing assay. Protein- and RNA splicing-dedicated in silico analyses were performed for all variants of unknown significance (VUS). Variants predicted as the ones most likely affecting pre-mRNA splicing were experimentally analyzed in a minigene assay.ResultsWe identified 48 women who were tested negative for their family’s path_BRCA1 (n = 13) or path_BRCA2 (n = 35) variants. Pathogenic variants in the ATM, BRCA2, MSH6 and MUTYH genes were found in 10% (5/48) of the cases, of whom 15% (2/13) were from path_BRCA1 and 9% (3/35) from path_BRCA2 families. Out of the 26 unique VUS, 3 (12%) were predicted to affect RNA splicing (APC c.721G > A, MAP3K1 c.764A > G and MSH2 c.815C > T). However, by using a minigene, assay we here show that APC c.721G > A does not cause a splicing defect, similarly to what has been recently reported for the MAP3K1 c.764A > G. The MSH2 c.815C > T was previously described as causing partial exon skipping and it was identified in this work together with the path_BRCA2 c.9382C > T (p.R3128X).ConclusionAll women in breast or breast/ovarian cancer kindreds would benefit from being offered genetic testing irrespective of which causative genetic variants have been demonstrated in their relatives.Electronic supplementary materialThe online version of this article (10.1186/s13053-018-0086-0) contains supplementary material, which is available to authorized users.

Results of multigene panel testing in familial cancer cases without genetic cause demonstrated by single gene testing

“…The study population was selected from the Hereditary Cancer Biobank (n = 161), which is part of the out-patient inherited cancer clinic from the Norwegian Radium Hospital (Norway) 21 and the Department of Genomic Medicine (n = 30) from the University of Manchester (United Kingdom) 12 .…”

“…1). Out of the 191 familial cancer patients, we have previously reported on 95 individuals (48 phenocopies, 34 familial CRC and 13 multiple early-onset cases) 12,22,23 . The current study added 96 new cases, including 81 familial BC cases, 9 phenocopies and 6 additional subjects having multiple early-onset cancer (Fig.…”

The BRCA1 c.4096+3A>G Variant Displays Classical Characteristics of Pathogenic BRCA1 Mutations in Hereditary Breast and Ovarian Cancers, But Still Allows Homozygous Viability

“…Other genetic and lifestyle/hormonal factors also modify these risks for mutation carriers, exemplified genetically by 26 single nucleotide polymorphisms (SNPs) associated with BC risk, and 11 with OC risk [8]. High-risk kindreds with a BRCA1 mutation may reflect the accumulation of such modifiers, and tested non-carriers in these families may, therefore, or for other reasons, be at elevated risk, or already be affected (known as phenocopies) [9,10]. In many ways, the BRCA2 gene/mutations can be described similarly, with high tissue-specific risks, and risk-modifying effects of lifestyle/hormonal factors, SNPs and three OCCRs in the gene [6,7,8,9,10].…”

“…High-risk kindreds with a BRCA1 mutation may reflect the accumulation of such modifiers, and tested non-carriers in these families may, therefore, or for other reasons, be at elevated risk, or already be affected (known as phenocopies) [9,10]. In many ways, the BRCA2 gene/mutations can be described similarly, with high tissue-specific risks, and risk-modifying effects of lifestyle/hormonal factors, SNPs and three OCCRs in the gene [6,7,8,9,10]. Importantly for the scope of this article, BRCA1 and BRCA2 are tumor-suppressor genes and, in accordance with Knudson’s two-hit model [11], the genotypes in tumors from mutation carriers typically show loss of heterozygosity (LOH), with preferential loss of the non-mutated or "wild-type" copy (wtLOH) of the gene, and its surrounding chromosomal region [12,13].…”

Novel Genetic Markers for Early Detection of Elevated Breast Cancer Risk in Women

“…Both mutations were predicted as pathogenic by our model (note that while p.Ala272Val mutation is reported to reduce protein function [40], this mutation is still reported as a mutation with unknown clinical significance based on variant classification guideline by the American College of Medical Genetics and Genomics(ACMG)). Furthermore, previously this mutation was mentioned in a patient with breast cancer, but the patient had p.R3128X in BRCA2 as well [41]). Referring to the clinical information of those two carries, the B2 patient had a high grade, stage I breast cancer, with the size of the tumor smaller than 1 cm.…”