Clinical testing of BRCA1 and BRCA2: a worldwide snapshot of technological practices

Toland, Amanda E.; Forman, Andrea; Couch, Fergus J.; Culver, Julie O.; Eccles, Diana; Foulkes, William D.; Hogervorst, Frans B.L.; Houdayer, Claude; Levy-Lahad, Ephrat; Monteiro, Alvaro N.A.; Neuhausen, Susan L.; Plon, Sharon E.; Sharan, Shyam K.; Spurdle, Amanda B.; Szabo, Csilla I.; Brody, Lawrence C.

doi:10.1038/s41525-018-0046-7

Cited by 52 publications

(35 citation statements)

References 14 publications

(8 reference statements)

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“…LRG ranges from very rare among Canadian and Finish families [27,28] to more than one-third of pathogenic alterations among families in northern Italy [29]. The multiplex ligation-dependent probe amplification (MLPA) is the most commonly used method for the identification of these alterations [30].…”

Section: Genetic Testing Developmentsmentioning

confidence: 99%

Germline Missense Variants in BRCA1: New Trends and Challenges for Clinical Annotation

Golubeva¹,

Nepomuceno²,

Monteiro³

2019

Preprint

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Genetic testing allows for identification of germline DNA variations which are associated with a significant increase in risk of developing breast and ovarian cancer. Detection of a BRCA1 or BRCA2 pathogenic variant triggers several clinical management actions, which may include increased surveillance and prophylactic surgery for healthy carriers or treatment with PARP inhibitor therapy for carriers diagnosed with cancer. Thus, standardized validated criteria for annotation of BRCA1 and BRCA2 variants according to their pathogenicity are necessary to support clinical decision making and ensure improved outcomes. Upon detection, variants whose pathogenicity can be inferred by the genetic code are typically classified as pathogenic, likely pathogenic, likely benign, or benign. Variants whose impact on function cannot be directly inferred by the genetic code are labeled as Variants of Uncertain Clinical Significance (VUS) and are evaluated by multifactorial likelihood models that use personal and family history of cancer, segregation data, prediction tools, and co-occurrence with a pathogenic BRCA variant. Missense variants, coding alterations that replace a single amino acid residue with another, are a class of variants for which determination of clinical relevance is particularly challenging. Here, we discuss current issues in variant classification by following a typical life cycle of a BRCA1 missense variant through detection, annotation and information dissemination. Advances in massively parallel sequencing have led to a substantial increase in VUS findings. Although comprehensive assessment and classification of missense variants according to their pathogenicity remains the bottle neck, new developments in functional analysis, high throughput assays, data sharing, and statistical models are rapidly changing this scenario.

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Section: Genetic Testing Developmentsmentioning

confidence: 99%

Germline Missense Variants in BRCA1: New Trends and Challenges for Clinical Annotation

Golubeva¹,

Nepomuceno²,

Monteiro³

2019

Preprint

Self Cite

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“…14,35 Technology approaches used by testing laboratories vary widely, with a recent study reporting that only a minority of laboratories conduct full intronic sequencing. 36 Our study demonstrates the utility of leveraging on functional characterization assays for reclassification of suspicious variants.…”

Section: Clinical Characteristicsmentioning

confidence: 81%

Investigation into the origins of an ancient BRCA1 founder mutation identified among Chinese families in Singapore

Shaw

Chan

Teo

et al. 2020

Intl Journal of Cancer

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Identification of ancestry-specific pathogenic variants is imperative for diagnostic, treatment, management and prevention strategies, and to understand penetrance/ modifiers on risk. Our study aimed to determine the clinical significance of a recurrent BRCA1 c.442-22_442-13del variant of unknown significance identified among 13 carriers from six Chinese families, all with a significant history of breast and/or ovarian cancer. We further aimed to establish whether this was due to a founder effect and explore its origins. Haplotype analysis, using nine microsatellite markers encompassing 2.5 megabase pairs around the BRCA1 locus, identified a common haploblock specific to the variant carriers, confirming a founder effect. Variant age was estimated to date back 77.9 generations to 69 BC using the Gamma approach. On principal component analysis using single nucleotide polymorphisms merged with 1000 Genomes dataset, variant carriers were observed to overlap predominantly with the southern Han Chinese population. To determine pathogenicity of the variant, we assessed the functional effect on RAD51 foci formation as well as replication fork stability upon induction of DNA damage and observed an impaired DNA repair response associated with the variant. In summary, we identified an ancient Chinese founder mutation dating back 77.9 generations, possibly common among individuals of southern Han Chinese descent. Using evidence from phenotypic/family history studies, segregation analysis and functional characterization, the BRCA1 variant was reclassified from uncertain significance to pathogenic.

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“…The consent forms were signed by donors to approve the use of the tissue for breast cancer research. Genetic testing of BRCA1 mutation was conducted by the hospital (Toland et al 2018). Using previously published protocols (Zhang et al 2017), fresh unfixed breast tissue was processed to generate single-cell suspension and the single cells were sorted into four fractions using FACS: EpCAM _…”

Section: Breast Tissuesmentioning

confidence: 99%

Cell-type-specific epigenomic variations associated withBRCA1mutation in pre-cancer human breast tissues

Hsieh

et al. 2020

Preprint

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BRCA1 germline mutation carriers are predisposed to breast cancers. Epigenomic regulations have been known to strongly interact with genetic variations and potentially mediate biochemical cascades involved in tumorigenesis. Due to the cell-type specificity of epigenomic features, profiling of individual cell types is critical for understanding the molecular events in various cellular compartments within complex breast tissue. Here we report cell-type-specific profiling of genome-wide histone modifications including H3K27ac and H3K4me3 in basal, luminal progenitor, mature luminal, and stromal cells extracted from pre-cancer BRCA1 mutation carriers and non-carriers, conducted using a low-input technology that we developed. We discover that basal and stromal cells present the most extensive epigenomic differences between mutation carriers (BRCA1mut/+) and non-carriers (BRCA1+/+) while luminal progenitor and mature luminal cells are relatively unchanged with the mutation. Furthermore, the epigenomic changes in basal cells due to BRCA1 mutation appear to facilitate their transformation into luminal progenitor cells. Our findings shed light on the pre-cancer epigenomic dynamics due to BRCA1 mutation and how they may contribute to eventual development of predominantly basal-like breast cancer.

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Clinical testing of BRCA1 and BRCA2: a worldwide snapshot of technological practices

Cited by 52 publications

References 14 publications

Germline Missense Variants in BRCA1: New Trends and Challenges for Clinical Annotation

Germline Missense Variants in BRCA1: New Trends and Challenges for Clinical Annotation

Investigation into the origins of an ancient BRCA1 founder mutation identified among Chinese families in Singapore

Cell-type-specific epigenomic variations associated withBRCA1mutation in pre-cancer human breast tissues

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