Factors predicting reclassification of variants of unknown significance

Wright, Moriah; Menon, Vijay G.; Taylor, Lindsay; Shashidharan, Maniamparampil; Westercamp, Twilla; Ternent, Charles A.

doi:10.1016/j.amjsurg.2018.08.008

Cited by 22 publications

(12 citation statements)

References 22 publications

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“…While there have been some functional studies to assess the pathogenicity of CHEK2 missense variants, larger studies are necessary to permit application of specific ACMG/AMP criteria (i.e., PS3) [ 32 , 59 , 61 , 62 , 63 ]. In the setting of paired tumor/normal sequencing inclusive of broad cancer-associated gene content and allowing for comprehensive analysis of the CHEK2 gene, variant classification may improve, further delineating which CHEK2 variants may impact cancer risk [ 64 , 65 , 66 ].…”

Section: Discussionmentioning

confidence: 99%

CHEK2 Alterations in Pediatric Malignancy: A Single-Institution Experience

Abdelghani

Schieffer

Cottrell

et al. 2023

Cancers

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Background: Approximately 10% of pediatric malignancies are secondary to germline alterations in cancer-predisposing genes. Checkpoint kinase 2 (CHEK2) germline loss-of-function variants have been reported in pediatric cancer patients, but clinical phenotypes and outcomes are poorly described. We present our single-institution experience of pediatric oncology patients with CHEK2 germline alterations, including clinical presentations and outcomes. Methods: Pediatric oncology patients with CHEK2 germline alterations were identified among those assessed by clinical or translational research at the Institute for Genomic Medicine at Nationwide Children’s Hospital. A chart review of disease course was conducted on identified patients. Results: We identified 6 patients with germline CHEK2 variants from a cohort of 300 individuals, including 1 patient with concurrent presentation of Burkitt lymphoma and neuroblastoma, 3 patients with brain tumors, 1 patient with Ewing sarcoma, and 1 patient with myelodysplastic syndrome. Three patients had a family history of malignancies. Four patients were in remission; one was undergoing treatment; one patient had developed treatment-related meningiomas. We review prior data regarding CHEK2 variants in this population, challenges associated with variant interpretation, and genetic counseling for individuals with CHEK2 variants. Conclusions: CHEK2 germline loss-of-function alterations occur in patients with a variety of pediatric tumors. Larger multicenter studies will improve our understanding of the incidence, phenotype, and molecular biology of CHEK2 germline variants in pediatric cancers.

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Section: Discussionmentioning

confidence: 99%

CHEK2 Alterations in Pediatric Malignancy: A Single-Institution Experience

Abdelghani

Schieffer

Cottrell

et al. 2023

Cancers

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“…Using these guidelines, several studies have reclassified BRCA1 and BRCA2 variants in Asian populations [ 79 – 81 ]. Given that that a positive family history increases the likelihood of variant reclassification, our goal is to use the ACMG guidelines to reclassify variants at high frequency in our high-risk BCa patients as reclassifications have a high potential for clinical impact often altering the clinical management of patients [ 82 ]. For example, Turner et al .…”

Section: Discussionmentioning

confidence: 99%

Hereditary variants of unknown significance in African American women with breast cancer

McDonald

Ricks-Santi²

2022

PLoS ONE

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Expanded implementation of genetic sequencing has precipitously increased the discovery of germline and somatic variants. The direct benefit of identifying variants in actionable genes may lead to risk reduction strategies such as increased surveillance, prophylactic surgery, as well as lifestyle modifications to reduce morbidity and mortality. However, patients with African ancestry are more likely to receive inconclusive genetic testing results due to an increased number of variants of unknown significance decreasing the utility and impact on disease management and prevention. This study examines whole exome sequencing results from germline DNA samples in African American women with a family history of cancer including 37 cases that were diagnosed with breast cancer and 51 family members. Self-identified ancestry was validated and compared to the 1000 genomes population. The analysis of sequencing results was limited to 85 genes from three clinically available common genetic screening platforms. This target region had a total of 993 variants of which 6 (<1%) were pathogenic or likely pathogenic, 736 (74.1%) were benign, and 170 (17.1%) were classified as a variant of unknown significance. There was an average of 3.4±1.8 variants with an unknown significance per individual and 85 of 88 individuals (96.6%) harbored at least one of these in the targeted genes. Pathogenic or likely pathogenic variants were only found in 6 individuals for the BRCA1 (p.R1726fs, rs80357867), BRCA2 (p.K589fs, rs397507606 & p.L2805fs, rs397507402), RAD50 (p.E995fs, rs587780154), ATM (p.V2424G, rs28904921), or MUTYH (p.G396D, rs36053993) genes. Strategies to functionally validate the remaining variants of unknown significance, especially in understudied and hereditary cancer populations, are greatly needed to increase the clinical utility and utilization of clinical genetic screening platforms to reduce cancer incidence and mortality.

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“…Overall variant and VUS reclassification rates reported in this study were 6.91% and 7.36% respectively. A range of VUS reclassification rates have been previously reported in literature which have ranged between 8 and 28% in reports from clinical cancer care settings, 7,9,[13][14][15] and anywhere between 6.9 and 66% in studies that report results from purposeful variant reclassification efforts, 16 and 24.9% in one report from a commercial laboratory. 17 Our results are consistent with results from other hospitals and genetic testing laboratories.…”

Section: Vusmentioning

confidence: 95%

“…VUS reclassification rates can vary based on a number of factors including patient characteristics such as ancestry 7 and differences in variant reinterpretation policies of genetic testing laboratories. 8 Number of family members with phenotypic disease, 9 and year of initial genetic testing (pre or post‐2015 American College of Medical Genomics guideline issuance 1 ) have also been reported as additional factors associated with higher reclassification rates.…”

Section: Introductionmentioning

confidence: 99%

A multicenter study of clinical impact of variant of uncertain significance reclassification in breast, ovarian and colorectal cancer susceptibility genes

et al. 2022

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Background Clinical interpretation of genetic test results is complicated by variants of uncertain significance (VUS) that have an unknown impact on health but can be clarified through reclassification. There is little empirical evidence regarding VUS reclassification in oncology care settings, including the prevalence and outcomes of reclassification, and racial/ethnic differences. Methods This was a retrospective analysis of persons with and without a personal history of cancer carrying VUS (with or without an accompanying pathogenic or likely pathogenic [P/LP] variant) in breast, ovarian, and colorectal cancer predisposition genes seen at four cancer care settings (in Texas, Florida, Ohio, and New Jersey) between 2013 and 2019. Results In 2715 individuals included in the study, 3261 VUS and 313 P/LP variants were reported; 8.1% of all individuals with VUS experienced reclassifications and rates varied significantly among cancer care settings from 4.81% to 20.19% (overall p < 0.001). Compared to their prevalence in the overall sample, reclassification rates for Black individuals were higher (13.6% vs. 19.0%), whereas the rates for Asian individuals were lower (6.3% vs. 3.5%) and rates for White and Hispanic individuals were proportional. Two‐year prevalence of VUS reclassification remained steady between 2014 and 2019. Overall, 11.3% of all reclassified VUS resulted in clinically actionable findings and 4.6% subsequently changed individuals' clinical managements. Conclusions The findings from this large multisite study suggest that VUS reclassification alters clinical management, has implications for precision cancer prevention, and highlights the need for implementing practices and solutions for efficiently returning reinterpreted genetic test results.

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Factors predicting reclassification of variants of unknown significance

Cited by 22 publications

References 22 publications

CHEK2 Alterations in Pediatric Malignancy: A Single-Institution Experience

CHEK2 Alterations in Pediatric Malignancy: A Single-Institution Experience

Hereditary variants of unknown significance in African American women with breast cancer

A multicenter study of clinical impact of variant of uncertain significance reclassification in breast, ovarian and colorectal cancer susceptibility genes

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