Reinterpretation of BRCA1 and BRCA2 variants of uncertain significance in patients with hereditary breast/ovarian cancer using the ACMG/AMP 2015 guidelines

So, Min Kyung; Jeong, Tae Dong; Lim, Woosung; Moon, Byung In; Paik, Nam Sun; Kim, Seung Cheol; Huh, Jungwon

doi:10.1007/s12282-019-00951-w

Cited by 40 publications

(39 citation statements)

References 34 publications

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“…To assess the pathogenicity of such variants accurately, the classification method must be based on a wide variety of evidence. Therefore, we reinterpreted all the 59 Class 1/2/4/5 variants (37 benign and 22 pathogenic) used in the MANO-B method according to the ACMG 2015 guidelines as previously described (Supplementary Table 1) 26,30 . As a result, 18 variants (31%), including R2842H and V2908G, were classified into VUSs because of insufficient evidence ( Supplementary Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

High-Throughput Functional Evaluation of BRCA2 Variants of Unknown Significance

Ikegami

Ueno

Momozawa

et al. 2020

Preprint

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Keywords: BRCA2, poly(ADP-ribose) polymerase (PARP) inhibitor, variants of unknown 22 significance (VUSs), companion diagnosis, Bayesian hierarchical model 23 24 ABSTRACT 44Numerous nontruncating missense variants of the BRCA2 gene have been identified, but there 45 is a lack of convincing evidence, such as familial data, demonstrating their clinical relevance 46 and they thus remain unactionable. To assess the pathogenicity of variants of unknown 47The BRCA1 and BRCA2 (BRCA) genes encode key proteins in the homology-directed DNA 60 break repair (HDR) pathway, and their inactivation predisposes individuals to cancer 61 development 1 . Germline loss-of-function variants in BRCA markedly increase the risk of early-62 onset breast and ovarian cancer; in such cases, prophylactic oophorectomy and mastectomy 63 and genetic testing for at-risk relatives must be considered 2, 3, 4 . Tumors with pathogenic 64 mutations within BRCA and defective HDR have been shown to be particularly sensitive to 65 platinum-based chemotherapies and PARP inhibitors, the efficacy of which is mediated 66 through synthetic lethality in cancer cells with BRCA loss-of-function 5, 6 . 67 68The American College of Medical Genetics and Genomics (ACMG) standards and guidelines 69 for the interpretation of sequence variants recommend a process for variant classification based 70 on criteria using population, computational, functional, and segregation data 7 . Family-based 71 studies including a multifactorial model of pathology, a cosegregation profile, and the 72 cooccurrence and family history of cancer may exemplify the most reliable methods for 73 classifying BRCA2 gene variants 8, 9 . Nonsense or frameshift mutations within the coding exons 74 of BRCA markedly alter the structures of the protein products and are presumed to confer loss-75 of-function. However, the vast majority of missense variants are individually rare in both 76 general populations and cancer patients, and case-control studies may not have sufficient 77 statistical significance to classify these variants as pathogenic or benign 10, 11, 12 . No current in 78 silico computational prediction algorithm for missense variants is accurate enough when used 79 alone 13 . Thus, the functional evaluation of missense variants of unknown significance (VUSs) 80 is urgently required to improve the interpretation of variants identified by genetic testing and 81 to support clinical decision-making for their carriers 14 . 82Page 5 of 63 While thousands of BRCA1 VUSs have been assessed by recently developed high-throughput 83 functional assays 15, 16, 17 , a few hundred BRCA2 variants have been evaluated by a conventional 84 functional assay for BRCA2, the HDR assay 18, 19 . The HDR assay has three issues requiring 85 improvement: (i) the throughput is quite low, (ii) it uses a hamster cell line with transient 86 expression of BRCA2 cDNA, and most importantly, (iii) it can evaluate only variants in the 87 DNA-binding domain 14, 20 . To overcome these limitations, we propose herein a high-8...

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Section: Resultsmentioning

confidence: 99%

High-Throughput Functional Evaluation of BRCA2 Variants of Unknown Significance

Ikegami

Ueno

Momozawa

et al. 2020

Preprint

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“…Several studies have shown that about 10%–15% of the cases tested for BRCA exhibited a pathogenic variant [ 20 ]. Further, previous studies have reported a range of prevalence for BRCA VUS (3.9%–22.5%) [ 7 8 9 10 11 21 22 ]. However, these results are primarily from breast cancer studies, as there are very few studies that have solely focused on gynecological oncology.…”

Section: Discussionmentioning

confidence: 99%

“…The field of genetic testing is rapidly expanding, and interpretation of results is a greater challenge now that a larger number of genetic VUS have been isolated [ 7 ]. In, South Korea, which is a unitary country, approximately 3.9%–24.6% of patients tested for BRCA1/2 possessed one or more VUS, primarily in breast cancer patients [ 8 9 10 11 12 ]. Although BRCA1 and BRCA2 gene testing plays a pivotal role in selecting treatment options for patients with hereditary gynecological cancer, VUS therapeutic decision-making faces constraints.…”

Section: Introductionmentioning

confidence: 99%

Reclassification of BRCA1 and BRCA2 variants found in ovarian epithelial, fallopian tube, and primary peritoneal cancers

Ryu

Shim

et al. 2020

J Gynecol Oncol

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Objective We investigated the proportions of and reclassified BRCA1/2 variants of unknown significance (VUS) in Korean patients with epithelial ovarian, tubal, and primary peritoneal cancers. Methods Data from 805 patients who underwent genetic testing for BRCA1/2 from January 1, 2006 to August 31, 2018 were included. The VUS in BRCA1/2 were reclassified using the 2015 American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines. Results A BRCA1 pathogenic variant was found in 17.0% (137/805) of the patients, and BRCA1 VUS were found in 15.9% (128/805) of the patients. Further, 8.7% (69/805) of the patients possessed a BRCA2 pathogenic variant and 18.4% (148/805) of the patients possessed BRCA2 VUS. Fifty-three specific BRCA1 VUS were found and 20 were further reclassified as benign (n=11), likely benign (n=5), likely pathogenic (n=3), and pathogenic (n=1). The remaining 33 remained classified as VUS. For BRCA2 , 55 specific VUS were detected; among these, 14 were reclassified as benign or likely benign, and 2 were reclassified as likely pathogenic. Among the 805 patients, 195 were found to have only VUS and no pathogenic variants (PV), and 41.5% (81/195) were reclassified as benign or likely benign, and 10.3% (20/195) as pathogenic or likely pathogenic variants. Conclusions Approximately 33.3% (36/108) of the specific BRCA1/2 variants analyzed in this study that were initially classified as VUS over a 13-year period were reclassified. Among these, 5.6% (6/108) were reclassified as pathogenic or likely pathogenic variants.

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“…So et al reported that 30/75 (40%) VUS patients were reclassi ed to "benign or likely benign" [17]. In our study, six patients with BRCA1 VUS (4 mutations) and three patients with BRCA2 VUS (2 mutations) were reclassi ed as "pathogenic or likely pathogenic".…”

Section: Discussionmentioning

confidence: 53%

“…In addition, several studies have suggested that this mutation is pathogenic based on other evidence including strong family history of breast and ovarian cancer, absence in general population data, impaired function demonstrated by in silico studies, and triple negativity in clinicopathologic features [16,17,23]. It is advisable to make management decisions based on 'likely pathogenic' variants.…”

Section: L1780p Interpretationmentioning

confidence: 99%

Analysis of BRCA1/2 variants of unknown significance in patients with breast cancer from a prospective KOHBRA study

Kim

Park

et al. 2020

Preprint

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Background Genetic testing for BRCA1 and BRCA2 genes is crucial for diagnosing hereditary breast and ovarian cancer syndromes (HBOC). Testing for such genes has been on the rise due to the development of multigene panel tests. However, results classified as variants of uncertain significance (VUS) present challenges to clinicians trying to interpret their functions and choose appropriate management plans.Methods We reviewed a total of 676 breast cancer patients who had VUS on BRCA mutation tests between November 2007 and April 2013 in the KOHBRA study. These results were compared to the ClinVar database. We calculated the incidence and odds ratios for these variants using the Korean Reference Genome Database (KRGDB).Results A total of 58 and 91 distinct VUS in BRCA1 and 2 were identified in the KOHBRA study (comprising 258 and 453 patients, respectively). A total of 27 variants in the KOHBRA study were not registered in the SNP database. Of the BRCA1 VUS, 20 variants were reclassified as benign or likely benign, 4 variants were reclassified as pathogenic or likely pathogenic, and 8 variants remained as VUS according to the ClinVar database. Of the BRCA2 VUS variants, 25 variants were reclassified as benign or likely benign, two variants were reclassified as pathogenic or likely pathogenic, and 33 variants remained as VUS according to the Clinvar database. There were 12 variants with conflicting interpretations of pathogenicity for BRCA1 and 18 variants for BRCA2. Among them, p.Leu1780Pro showed a particularly high odds ratio.Conclusions Six pathogenic variants and one conflicting variant identified using ClinVar could be reclassified as pathogenic variants in this study. Using updated ClinVar and calculating odds ratios can be helpful when reclassifying VUS in BRCA1/2.

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Reinterpretation of BRCA1 and BRCA2 variants of uncertain significance in patients with hereditary breast/ovarian cancer using the ACMG/AMP 2015 guidelines

Cited by 40 publications

References 34 publications

High-Throughput Functional Evaluation of BRCA2 Variants of Unknown Significance

High-Throughput Functional Evaluation of BRCA2 Variants of Unknown Significance

Reclassification of BRCA1 and BRCA2 variants found in ovarian epithelial, fallopian tube, and primary peritoneal cancers

Analysis of BRCA1/2 variants of unknown significance in patients with breast cancer from a prospective KOHBRA study

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