Impact of amino acid substitutions at secondary structures in the BRCT domains of the tumor suppressor BRCA1: Implications for clinical annotation

Fernandes, Vanessa C.; Golubeva, Volha A.; Pietro, Giuliano Di; Shields, Cara E.; Amankwah, Kwabena; Nepomuceno, Thales C.; Gregoriis, Giuliana De; Abreu, Renata B. V.; Harro, Carly M.; Gomes, Thiago T.; Silva, Ricceli F.; Suarez‐Kurtz, Guilherme; Couch, Fergus J.; Iversen, Edwin S.; Monteiro, Alvaro N.A.; Carvalho, Marcelo A.

doi:10.1074/jbc.ra118.005274

Cited by 39 publications

(68 citation statements)

References 41 publications

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“…BRCA1 c.5470_5477del is a frameshift mutation located in the region encoding the BRCT domain of BRCA1, which is an integral signaling module in the DNA damage response 26 and crucial for transcriptional activation. [27][28][29] This may explain why the carriers of BRCA1 c.5470_5477del tended to be associated with particularly aggressive BC. The BRCA1 c.5470_5477del mutated BC patients tended to have poorer survival than the carriers of other BRCA1 pathogenic variants.…”

Section: Discussionmentioning

confidence: 99%

BRCA1 c.5470_5477del, a founder mutation in Chinese Han breast cancer patients

Meng

Yao

Yuan

et al. 2020

Intl Journal of Cancer

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The spectrum and frequency of BRCA1/2 pathogenic variants may be ethnicity‐specific. Whether high‐frequency founder mutations are present in Chinese women remains largely unknown. In the current study, germline pathogenic variants in the BRCA1/2 genes were determined in 9,505 unselected Chinese Han breast cancer (BC) patients by next‐generation and/ or Sanger sequencing. Four hundred and seventy‐one (5.0%) BC patients carried BRCA1/2 pathogenic variants in this cohort. A total of 25 recurrent pathogenic variants (at least found in four unrelated patients) were identified in this cohort (8 BRCA1 and 17 BRCA2 recurrent pathogenic variants), 161 patients carried one of these recurrent pathogenic variants in this cohort of 9,505 patients. All of these 25 recurrent pathogenic variants were further explored whether they had founder effect through haplotype analysis. The most common pathogenic variant, BRCA1 c.5470_5477del, was found in 30 BC patients from 29 unrelated families. Twenty‐seven of these 29 unrelated patients who carried this BRCA1 c.5470_5477del mutation shared an identical haplotype, indicating that BRCA1 c.5470_5477del was a founder mutation in the Chinese Han population. Furthermore, BRCA1 c.5470_5477del mutation carriers had a significantly worse survival than noncarriers (disease‐free survival, p = 0.049; overall survival, p = 0.029). Taken together, our data suggested that BRCA1 c.5470_5477del is a founder mutation in the Chinese Han population and BRCA1 c.5470_5477del mutation carriers have a poor survival.

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Section: Discussionmentioning

confidence: 99%

BRCA1 c.5470_5477del, a founder mutation in Chinese Han breast cancer patients

Meng

Yao

Yuan

et al. 2020

Intl Journal of Cancer

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“…Throughout the years, several functional assays have been proposed to evaluate the impact of variants on BRCA1 biological roles and biochemical properties (E3 ubiquitin ligase activity, cell cycle control, genotoxic agent sensibility, phosphopeptide binding, protease sensitivity and others) [56]. For variants in the carboxy-terminus of BRCA1 all assays display high specificity (80-100%) but more variable sensitivity (63-100%) with lower sensitivity seen in yeast-based presumably due to pathogenic variants which are stable at lower temperatures [57]. The high sensitivity and specificity found for most mammalian-based assays allow for the use of functional data in classifying VUS.…”

Section: Functional Assaysmentioning

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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“…Findlay et al 3 , exploited the essentiality of BRCA1 for cell survival by used a saturating genome editing approach in HAP1 cells to evaluate nearly 4,000 SNVs (n=1837 distinct missense). Finally, Fernandes et al 4 , reported on analysis of 354 distinct missense variants (n=79 in IARC classes 0 or 1 [benign] or 4,5 [pathogenic]) in the BRCT domain of BRCA1 using a validated transcriptional assay. Combined with results from a homology directed repair assay of 207 missense variants in the DNA binding domain of BRCA2, 5 there are now sufficient numbers of variants to apply supervised learning methods to better predict damaging mutations in BRCA1 and BRCA2.…”

Section: Introductionmentioning

confidence: 99%

Prediction of the functional impact of missense variants in BRCA1 and BRCA2 with BRCA-ML

Hart

Polley

Shimelis

et al. 2019

Preprint

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AbstractIn silico predictions of missense variants is an important consideration when interpreting variants of uncertain significance (VUS) in the BRCA1 and BRCA2 genes. We trained and evaluated hundreds of machine learning algorithms based on results from validated functional assays to better predict missense variants in these genes as damaging or neutral. This new optimal “BRCA-ML” model yielded a substantially more accurate method than current algorithms for interpreting the functional impact of variants in these genes, making BRCA-ML a valuable addition to data sources for VUS classification.

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Impact of amino acid substitutions at secondary structures in the BRCT domains of the tumor suppressor BRCA1: Implications for clinical annotation

Cited by 39 publications

References 41 publications

BRCA1 c.5470_5477del, a founder mutation in Chinese Han breast cancer patients

BRCA1 c.5470_5477del, a founder mutation in Chinese Han breast cancer patients

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

Prediction of the functional impact of missense variants in BRCA1 and BRCA2 with BRCA-ML

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