Follow-up of carriers of BRCA1 and BRCA2 variants of unknown significance: Variant reclassification and surgical decisions

10002 Background: BRCA1 and BRCA2 mutations in the general population are rare. Women with these mutations have a significantly increased risk of invasive breast and ovarian cancer (65–85% and 15–65% cumulative lifetime risk, respectively). Variants of unknown significance (VUS), which are of uncertain clinical importance, account for up to 50% of all identified BRCA1 and BRCA2 sequence alterations1. Methods: Pooled data from all patients presenting to Fox Chase Cancer Center for genetic counseling was examined. Patients underwent genetic testing after detailed genetic counseling. Clinical data, including gender, ethnic background, and personal history of cancer, and total number of patients tested were collected. Results: A total of 1,765 women and 236 men underwent genetic testing. The distribution of ethnicity was: <1% Asian, 2.7% African American, <1% Hispanic, 2.4% other or of more than one ethnicity, 83% White, and 11% unknown. Mutations of BRCA1 and BRCA2 were seen in 13% of the women and 2.7% of the men. VUS were seen in 6.2% of the women and .15% of the men. Of the women positive for a VUS, 2.4% were Asian, 18.1% were African American, 5.5% were Hispanic, 4.7% were more than one ethnicity, 66.9% were White, and 2.4% were Unknown ethnicity. Only .15% of the men tested were positive for a VUS, all of whom were White. Of the 51 African American women tested, 45.1% were positive for a VUS while only 5.5% of the 1,503 White women tested were positive (p<0.0001). Of the females testing positive for a VUS, a personal history of breast cancer was seen in 66.7% of Asians, 78.3% of African Americans, 100% of Hispanics, 83.3% of those more than one race, 61% of Whites, and none of the people of unknown ethnic origin. One of three men testing positive for a VUS reported a history of breast cancer. Conclusions: Identification of VUS occurred disproportionately in African Americans, occurring ten times more often in African American women than White women in our study. Studies to improve classification of VUS as deleterious or neutral are needed to enhance the utility of genetic testing for women at risk, particularly those of African American ethnicity. 1Goldman, DE et al. Am. J. Hum. Genet., 2004. No significant financial relationships to disclose.

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Next-generation sequencing approach to hyperCKemia

Neurology Genetics ◽

10.1212/nxg.0000000000000352 ◽

2019 ◽

Vol 5 (5) ◽

pp. e352 ◽

Cited By ~ 4

Author(s):

Anna Rubegni ◽

Alessandro Malandrini ◽

Claudia Dosi ◽

Guja Astrea ◽

Jacopo Baldacci ◽

...

Keyword(s):

Next Generation Sequencing ◽

Molecular Diagnosis ◽

Diagnostic Yield ◽

Clinical Neurology ◽

Next Generation ◽

Variants Of Unknown Significance ◽

Unknown Significance ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing

ObjectiveNext-generation sequencing (NGS) was applied in molecularly undiagnosed asymptomatic or paucisymptomatic hyperCKemia to investigate whether this technique might allow detection of the genetic basis of the condition.MethodsSixty-six patients with undiagnosed asymptomatic or paucisymptomatic hyperCKemia, referred to tertiary neuromuscular centers over an approximately 2-year period, were analyzed using a customized, targeted sequencing panel able to investigate the coding exons and flanking intronic regions of 78 genes associated with limb-girdle muscular dystrophies, rhabdomyolysis, and metabolic and distal myopathies.ResultsA molecular diagnosis was reached in 33 cases, corresponding to a positive diagnostic yield of 50%. Variants of unknown significance were found in 17 patients (26%), whereas 16 cases (24%) remained molecularly undefined. The major features of the diagnosed cases were mild proximal muscle weakness (found in 27%) and myalgia (in 24%). Fourteen patients with a molecular diagnosis and mild myopathic features on muscle biopsy remained asymptomatic at a 24-month follow-up.ConclusionsThis study of patients with undiagnosed hyperCKemia, highlighting the advantages of NGS used as a first-tier diagnostic approach in genetically heterogeneous conditions, illustrates the ongoing evolution of molecular diagnosis in the field of clinical neurology. Isolated hyperCKemia can be the sole feature alerting to a progressive muscular disorder requiring careful surveillance.

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The Value of Next-Generation Sequencing in the Screening and Evaluation of Hematologic Neoplasms in Clinical Practice

American Journal of Clinical Pathology ◽

10.1093/ajcp/aqz203 ◽

2019 ◽

Vol 153 (5) ◽

pp. 639-645 ◽

Cited By ~ 1

Author(s):

Victoria Northrup ◽

Allison Maybank ◽

Nancy Carson ◽

Tarek Rahmeh

Keyword(s):

Next Generation Sequencing ◽

Next Generation ◽

Hematologic Neoplasms ◽

Clinical Value ◽

Variants Of Unknown Significance ◽

Myeloid Neoplasms ◽

Unknown Significance ◽

Conventional Cytogenetics ◽

Generation Sequencing

Abstract Objectives The implementation of next-generation sequencing (NGS) in routine clinical hematology practice remains limited. We evaluate the clinical value of NGS in the screening, diagnosis, and follow-up in hematologic neoplasms. Methods A targeted NGS panel was used to assess a total of 178 patients for questionable or previously diagnosed myeloid neoplasms. Results Gene variants were identified in 53% of patients. Novel variants were identified in 29% of patients and variants of unknown significance in 34%. Bone marrow samples yielded a higher number of variants than in peripheral blood. NGS is a more sensitive test than conventional cytogenetics. In several cases, NGS played a key role in the screening, diagnostics, prognostic stratification, and the clinical follow-up of a wide variety of myeloid neoplasms. Conclusions NGS is an effective tool in the evaluation of suspected and confirmed hematologic neoplasms and could become part of the routine workup of patients.

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In silico analysis of BRCA1 and BRCA2 missense variants and the relevance in molecular genetic testing

Scientific Reports ◽

10.1038/s41598-021-88586-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Kok-Siong Poon

Keyword(s):

Genetic Testing ◽

Molecular Genetic ◽

In Silico Analysis ◽

Molecular Testing ◽

Brca1 And Brca2 ◽

Missense Variants ◽

Variants Of Unknown Significance ◽

Sorting Intolerant From Tolerant ◽

Unknown Significance ◽

High Concordance

AbstractOver the years since the genetic testing of BRCA1 and BRCA2 has been conducted for research and later introduced into clinical practice, a high number of missense variants have been reported in the literature and deposited in public databases. Polymorphism Phenotyping v2 (PolyPhen-2) and Sorting Intolerant from Tolerant (SIFT) are two widely applied bioinformatics tools used to assess the functional impacts of missense variants. A total of 2605 BRCA1 and 4763 BRCA2 variants from the ClinVar database were analysed with PolyPhen2 and SIFT. When SIFT was evaluated alongside PolyPhen-2 HumDiv and HumVar, it had shown top performance in terms of negative predictive value (NPV) (100%) and sensitivity (100%) for ClinVar classified benign and pathogenic BRCA1 variants. Both SIFT and PolyPhen-2 HumDiv achieved 100% NPV and 100% sensitivity in prediction of pathogenicity of the BRCA2 variants. Agreement was achieved in prediction outcomes from the three tested approaches in 55.04% and 68.97% of the variants of unknown significance (VUS) for BRCA1 and BRCA2, respectively. The performances of PolyPhen-2 and SIFT in predicting functional impacts varied across the two genes. Due to lack of high concordance in prediction outcomes among the two tested algorithms, their usefulness in classifying the pathogenicity of VUS identified through molecular testing of BRCA1 and BRCA2 is hence limited in the clinical setting.

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Interpreting Osteogenesis Imperfecta Variants of Uncertain Significance in the Context of Physical Abuse: A Case Series

Journal of Pediatric Genetics ◽

10.1055/s-0038-1672135 ◽

2018 ◽

Vol 08 (02) ◽

pp. 063-068

Author(s):

Jennifer Canter ◽

Vinod Rao ◽

Vincent Palusci ◽

David Kronn ◽

Michal Manaster ◽

...

Keyword(s):

Child Abuse ◽

Osteogenesis Imperfecta ◽

Physical Abuse ◽

Clinical Significance ◽

Case Series ◽

Variants Of Unknown Significance ◽

Unknown Significance ◽

Potential Abuse ◽

Uncertain Significance

AbstractUnexplained childhood fracture(s) warrant consideration of physical abuse and osteogenesis imperfecta (OI). Genetic OI testing may identify “variants of unknown significance (VUS).” Interpretation of VUS in context of potential abuse may have protective, criminal, and medical impacts. This case series explores practices regarding clinicians' interpretation of VUS during child abuse evaluations. Variability was noted regarding factors considered for interpreting clinical significance. Based on these cases, recommendations for careful and thorough evaluation are detailed, including proposed use of a limited follow-up skeletal survey in 3 months, as a consideration to assess healing of prior fractures and to look for any additional injuries.

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The importance of variants of unknown significance (VUS) in BRCA mutation.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e22507 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e22507-e22507

Author(s):

N Mullai

Keyword(s):

Breast Cancer ◽

Ovarian Cancer ◽

Brca Mutation ◽

Brca1 And Brca2 ◽

Management Options ◽

Brca Mutations ◽

Variants Of Unknown Significance ◽

Family Histories ◽

Unknown Significance ◽

Brca2 Mutations

e22507 Background: Genetic testing of patients for BRCA mutation may report variants of unknown significance (VUS). The use of multi-gene panels in clinical care has been increasing. Consequently, the reporting of variants of unknown significance has also increased. More than two decades of research and testing have elevated the status of BRCA1 and BRCA2 genes as the most well characterized genes. However, VUS are found even in BRCA1/2 testing. This raises many ethical and policy issues including communicating the significance of the results and possible clinical management options to patients. The practicing physicians would face the ethical and potential legal burden of contacting and explaining to patients, when any role of VUS changes and gets reclassified as potentially harmful. Methods: Data were collected retrospectively from medical records of patients tested for BRCA mutations. The results of fifty-two patients were analyzed. Eight patients had BRCA1 and BRCA2 mutations and twelve patients had variants of unknown significance. Results: When the results of thirteen patients with BRCA mutations with VUS were analyzed further, the variants included POLE, CHEK2, PALB2, MUTHYH, BR1P1, MSH3, ATM, RAD51C, GALNT12, etc. The age of these patients ranged from 39 years to 69 years. Four patients had ovarian cancer and eight patients had breast cancer, and one patient had both breast and ovarian cancers. The number of patients with stage IV, III, II, and I diseases were six, one, two, and two respectively. One patient had bilateral breast cancer and one patient had carcinoma in-situ. Eight patients had family histories of various cancers, including cancers of the breast, uterine, and prostate cancer. All patients were treated appropriately and three patients died due to their disease. Conclusions: Based on patients’ age, family histories, and disease characteristics BRCA mutation analyses were done. All patients tested positive for BRCA mutations and VUS were informed about their results. Variants of BRCA1 and BRCA2 occur in 2%-4% of tests depending on the laboratories, where the tests were performed. There is no concordance as to how VUS results were reported. There is conflicting evidence regarding the pathogenicity of VUS. These make clinical recommendations very complex. Based on existing guidelines, physicians can explain the details of the significance of BRCA! And BRCA2 mutations to patients with clarity. However, it is difficult and unclear to give recommendations regarding prophylactic measures, specific treatment options for BRCA mutation positive breast and ovarian cancer, follow-ups, and family testing in patients with VUS. Therefore, during BRCA testing, when VUS are reported routinely along with mutations of known significance, the treating physicians would need a better guidance to advise their patients without unduly increasing their anxiety, fear, and potential for misunderstanding.

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