Prevalence of BRCA1/2 mutations among an Irish cohort unrestricted by testing eligibility thresholds.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e13013-e13013
Author(s):  
Michael Conroy ◽  
David James Gallagher ◽  
Michael P. Farrell
Keyword(s):  
Genetic Testing ◽  
Brca1 Mutation ◽  
Brca2 Mutation ◽  
Diagnostic Testing ◽  
Retrospective Chart Review ◽  
Scoring Systems ◽  
National Guidelines ◽  
Variant Of Uncertain Significance ◽  
Uncertain Significance ◽  
Age Of Diagnosis

e13013 Background: Diagnostic criteria for BRCA1/2 genetic testing vary worldwide. Different eligibility thresholds for testing are used in different healthcare systems. In the public system in Ireland, this threshold is based on the Manchester Score (MS), with a score of ≥16 (approximately 10% likelihood of BRCA1/2 mutation) required for testing. Individuals unaffected by cancer are not eligible for diagnostic testing. Testing is also available privately by self-paying. We reviewed all self-pay patients in Ireland who were unrestricted by national guidelines. Methods: We performed a retrospective chart review of results from BRCA1/2 genetic testing in the Mater Private Hospital genetics clinic. Outcomes were recorded as ‘positive’, ‘wild type’ or ‘variant of uncertain significance’ (VUS). Results: 276 patients underwent testing between 2011 and 2016. 203 were affected with a median age of diagnosis of 48 (range 14-76), and 73 were unaffected individuals with a median age of 45 (range 30-74) at testing. 103 affected patients had a MS of ≥ 16: 7(6.8%) tested positive for BRCA1 mutation and 11(10.7%) tested positive for a BRCA2 mutation. Seven (6.8%) had a VUS characterised. 100 affected patients had an MS of <16: 3(3%) tested positive for a BRCA1 mutation and 5(5%)tested positive for a BRCA2 mutation. Eight (8%) had a VUS identified. 39 unaffected individuals had a MS ≥ 16: 6(15.4%) tested positive for a BRCA1 mutation, and 1(2.6%) for a BRCA2 mutation. 5(12.8%) had a VUS. 34 unaffected patients had an MS of <16: 2 (5.8%) tested positive for a BRCA2 mutation and 1 (2.9%) had a VUS. A total of 134 patients had a MS<16, and the prevalence of BRCA1/2 mutation in this group was 7% (n=10). Conclusions: The mutation detection rate was higher than expected in unaffected individuals and individuals belonging to families with MS < 16. Scoring systems such as the MS help to prioritise resources but miss many BRCA1/2 mutation carriers. [Table: see text]

Knowledge outcomes in a randomized trial of telephone vs. in-person disclosure of genetic testing: The COGENT study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1534-1534
Author(s):  
Nina Beri ◽  
Linda J. Patrick-Miller ◽  
Brian L. Egleston ◽  
Olufunmilayo I. Olopade ◽  
Michael J. Hall ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Randomized Trial ◽  
Genetic Knowledge ◽  
True Negative ◽  
Variant Of Uncertain Significance ◽  
Knowledge Change ◽  
Negative Results ◽  
Genetic Test Results ◽  
Uncertain Significance ◽  
Multivariable Analyses

1534 Background: Telephone disclosure (TD) of genetic testing is non-inferior to in-person disclosure (IPD) for most outcomes but did not meet non-inferiority for knowledge change. We sought to understand which concepts patients don’t understand and factors associated with lower knowledge. Methods: Patients were recruited to a multi-center, randomized trial (NCT01736345) comparing TD to IPD of genetic test results. 819 patients were randomized (IPD = 418; TD = 401); 165 declined randomization and requested IPD. Knowledge was assessed after pre-test counseling (V1) and test disclosure (V2). Results: There were no significant differences in genetic or multi-gene (MG) knowledge between disclosure groups after V1 and V2. On average, patients answered 73% (SD 1.19) of genetic knowledge and 57% (SD 1.78) of mg knowledge items correctly.After V1, most understood implications of a positive result (87%), that results are not deterministic (84%) and risks for their children (91%). Understanding of uninformative negative, true negative and variant of uncertain significance (VUS) results was lower (post-V1: 33%, 65%, 29%; post-V2 : 37%, 65%, 25%). In multivariable analyses, lower genetic knowledge after V1 was associated with study site, being older (p < 0.01), single (p < 0.01), non-white (p < 0.01), not Ashkenazi Jewish (p = 0.01), and not having a mutation in the family (p = 0.03), having more relatives with cancer (p < 0.01) and not graduating college (p < 0.01). Lower mg knowledge after V1 was associated with site and being non-white (p = 0.01). Lower genetic knowledge after V2 was not associated with disclosure method but associated with study site, being older (p < 0.01), not graduating college (p < 0.01) and being non-white (p < 0.01). Lower mg knowledge after V2 was only associated with not graduating college (p = 0.02). Conclusions: While there were no significant differences in genetic knowledge by disclosure method, understanding of several concepts (e.g. VUS and negative results) were lower regardless of arm. Several factors, including age, education and race/ethnicity were associated with lower knowledge. Interventions to improve genetic knowledge in real-world and diverse populations are needed. Clinical trial information: NCT07136345.

Higher prevalence of BRCA2 mutations among Chinese breast cancer patients in a community oncology clinic.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e12017-e12017
Author(s):  
Yi-Kong Keung ◽  
Adriana Hu ◽  
Annie Yeung ◽  
Amy Chan ◽  
Eddie Hu
Keyword(s):  
Breast Cancer ◽  
Family History ◽  
Brca1 Mutation ◽  
Brca2 Mutation ◽  
Small Sample ◽  
Brca1 And Brca2 ◽  
Similar Frequency ◽  
Nccn Guidelines ◽  
Uncertain Significance ◽  
Brca2 Mutations

e12017 Background: According to a large US population-based study, BRCA1 and 2 mutations occur in about 6 and 4% breast cancer cases age <45. Asians have the lowest prevalence of BRCA1 mutation among five US racial groups. The prevalence of BRCA1 and BRCA2 mutations was reported as 8.1% and 2.7% among pts with family history in Shanghai, compared to 4.9% and 7.5% respectively in Hong Kong. We would like to explore the BRCA mutations in a clinic located in an Asian-majority community in California. Methods: Consecutive female breast cancer pts selected for BRCA testing according to NCCN guidelines are retrospectively studied from 10/2009 to 10/2011. Sequencing of all translated exons and immediately adjacent intronic regions of the BRCA1 and BRCA2 was performed on the peripheral blood (Myriad, Utah). Results: Twenty-six pts were included in this study. Six pts have bilateral breast cancers; 2 synchronous and 4 metachronous with intervals of 11-13 years. Nine pts (34.6%) had BRCA2 germline mutations, of which 5 were considered deleterious and 4 of uncertain significance. Eleven pts (42.3%) had no BRCA mutation. BRCA results were unavailable in six pts because they were either not yet done or denied by health insurance. Conclusions: 1. High prevalence of BRCA2 mutation is seen in our pts selected according to NCCN guidelines. The presence of BRCA2 but not BRCA1 mutation in our study is intriguing. 2. Triple negative breast cancer is not more prevalent in BRCA2 mutation carriers. 3. Similar frequency of family history of breast/ovarian cancer is noted among pts with or without BRCA2 mutation, deleterious or of uncertain significance. The role of the BRCA2 mutation of uncertain significance needs to be further elucidated. 4. Due to the small sample size, further study is required to confirm our findings. [Table: see text]

scholarly journals Logistics and Uptake of Genetic Testing for Patients Referred for Telegenetic Counselling for Cancer

2018 ◽  
Vol 6 ◽  
Author(s):  
Kate Parks Shane-Carson ◽  
Cortlandt Martin
Keyword(s):  
Genetic Testing ◽  
Pathogenic Mutation ◽  
Ohio State University ◽  
State University ◽  
Completion Rates ◽  
Variant Of Uncertain Significance ◽  
Counselling Session ◽  
Uncertain Significance ◽  
The Ohio State University

Purpose:  There is a dearth of information about the uptake of genetic testing after telegenetic (videoconference) counselling for hereditary cancer, which has been previously reported as a limitation of this service delivery model.  Methods:  We performed a review of the triage list for patients referred to The Ohio State University (OSU) from two community cancer centres for telegenetic counselling appointments from April 1, 2014 to May 31, 2016.  Results:  A total of 179 patients were referred for telegenetic counselling, and of   these 62.6% (112/179) completed a 30-60 minute telegenetic counselling appointment.   Of those counselled, 82.1% (92/112) completed genetic testing,    12.0% (11/92) of whom were found to have a pathogenic mutation.  Of those with mutations, 45.5% (5/11) returned for a follow-up telegenetic counselling session to review results in more detail.  In addition, 18.5% (17/92) of patients tested had at least one variant of uncertain significance (VUS). Conclusions:  The presence of a nurse/nurse practitioner with the patient at the remote site during the telegenetic counselling session may have facilitated higher completion rates for genetic testing compared to previous reports in the literature, and appropriateness of genetic testing in this method of providing genetic counselling is reflected in the rates of results identifying deleterious mutations and variants of uncertain significance.

Genetic testing referral, uptake, and results in a program for women age 40 or younger with breast cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1542-1542
Author(s):  
Asma Ali ◽  
Ellen Warner ◽  
Kimberley Hill
Keyword(s):  
Breast Cancer ◽  
Genetic Testing ◽  
Young Women ◽  
Epidemiological Data ◽  
The Other ◽  
Brca Testing ◽  
Variant Of Uncertain Significance ◽  
Mutation Carriers ◽  
Uncertain Significance ◽  
Testing Uptake

1542 Background: PYNK: Breast Cancer Program for Young Woman is a novel program started in 2008 at our center to optimize management and promote research for women ≤ age 40 newly diagnosed with breast cancer. Clinical and epidemiological data including cancer family history (FH) is prospectively collected on each consenting patient. As Toronto’s population is uniquely multiethnic we sought to determine BRCA testing eligibility, uptake and results for PYNK patients. Methods: Of the 145 consecutive patients, data were available for 109, of whom 2 had testing prior to diagnosis. Our provincial BRCA testing criteria are age < 35 at diagnosis; suspicious FH; or Ashkenazi Jewish (AJ) and age < 50 at diagnosis. Results: Of the 107 previously untested patients, 40 were < 35 at diagnosis. In 5 of the other 67 testing eligibility could not be assessed. 66 of the 102 (65%) were eligible and of those 65 (98%) were offered referral for counseling. One declined counseling, 9 were not yet seen, 2 declined testing, and 53 were tested. Test results are available for 47 as follows: 30 (64%) no mutation, 4 (8%) variant of uncertain significance (VUS), 7(15%) BRCA1 mutations and 6 (13%) BRCA2 mutations including 1 of the 4 AJ women. Ethnicity of the other 12 mutation carriers was: 1 Hispanic, 2 European, 2 African, 4 Asians, 1 mix, 1 unknown and 1 not recorded. Two (15%) of the mutation carriers had no FH of breast or ovarian cancer. Four additional women opted for counseling and testing despite ineligibility and none had mutations. Conclusions: A specialized program for young women facilitates appropriate referral for genetic testing and encourages high testing uptake, which is important given the high prevalence of mutations (28% of tested women). Further research is necessary to assess the psychological and management impact of having a VUS on young women compared to their older counterparts.

scholarly journals Pathogenic Intronic Splice-Affecting Variants in MYBPC3 in Three Patients with Hypertrophic Cardiomyopathy

2021 ◽  
Vol 11 (2) ◽  
pp. 73-83
Author(s):  
Katherine A. Wood ◽  
Jamie M. Ellingford ◽  
James Eden ◽  
Huw B. Thomas ◽  
Raymond T. O’Keefe ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Diagnostic Testing ◽  
Wild Type ◽  
Variant Of Uncertain Significance ◽  
Common Causes ◽  
Uncertain Significance ◽  
Errors Analysis ◽  
The Impact ◽  
Intronic Variants

Genetic variants in MYBPC3 are one of the most common causes of hypertrophic cardiomyopathy (HCM). While variants in MYBPC3 affecting canonical splice site dinucleotides are a well-characterised cause of HCM, only recently has work begun to investigate the pathogenicity of more deeply intronic variants. Here, we present three patients with HCM and intronic splice-affecting MYBPC3 variants and analyse the impact of variants on splicing using in vitro minigene assays. We show that the three variants, a novel c.927-8G>A variant and the previously reported c.1624+4A>T and c.3815-10T>G variants, result in MYBPC3 splicing errors. Analysis of blood-derived patient RNA for the c.3815-10T>G variant revealed only wild type spliced product, indicating that mis-spliced transcripts from the mutant allele are degraded. These data indicate that the c.927-8G>A variant of uncertain significance and likely benign c.3815-10T>G should be reclassified as likely pathogenic. Furthermore, we find shortcomings in commonly applied bioinformatics strategies to prioritise variants impacting MYBPC3 splicing and re-emphasise the need for functional assessment of variants of uncertain significance in diagnostic testing.

Is the variant of uncertain significance (VUS) rate important in genetic testing for breast cancer?

2018 ◽  
Vol 44 (6) ◽  
pp. 875
Author(s):  
Gordon Wishart ◽  
Stewart Payne ◽  
Zoe Allen ◽  
Matthew Edwards ◽  
Vicki Kiesel
Keyword(s):  
Breast Cancer ◽  
Genetic Testing ◽  
Variant Of Uncertain Significance ◽  
Uncertain Significance

scholarly journals The Probability of Pathogenicity in Clinical Genetic Testing: A Solution for the Variant of Uncertain Significance

2016 ◽  
Vol 5 (4) ◽  
pp. 52
Author(s):  
Michael Gollob ◽  
Jeffrey S. Rosenthal ◽  
Kevin Thorpe
Keyword(s):  
Genetic Testing ◽  
Genetic Variant ◽  
Rare Variants ◽  
Direct Calculation ◽  
Medical Genetics ◽  
Clinical Genetic ◽  
Rare Genetic Variant ◽  
Variant Of Uncertain Significance ◽  
Clinical Genetic Testing ◽  
Uncertain Significance

We present a direct calculation for determining the probability that a rare genetic variant is the cause of an observed disease, under appropriate assumptions, in terms of the joint prevalence of the disease and of rare variants.  Our calculation provides a resolution of the so-called ``variant of unknown (or uncertain) significance'' problem, which has plagued medical genetics researchers.

scholarly journals National Estimates of Genetic Testing in Women With a History of Breast or Ovarian Cancer

2017 ◽  
Vol 35 (34) ◽  
pp. 3800-3806 ◽  
Author(s):  
Christopher P. Childers ◽  
Kimberly K. Childers ◽  
Melinda Maggard-Gibbons ◽  
James Macinko
Keyword(s):  
Ovarian Cancer ◽  
Genetic Testing ◽  
Unmet Need ◽  
Cancer Control ◽  
The United States ◽  
Eligibility Criteria ◽  
Cross Sectional ◽  
Age Of Diagnosis ◽  
History Of ◽  
Interview Survey

Purpose In the United States, 3.8 million women have a history of breast (BC) or ovarian cancer (OC). Up to 15% of cases are attributable to heritable mutations, which, if identified, provide critical knowledge for treatment and preventive care. It is unknown how many patients who are at high risk for these mutations have not been tested and how rates vary by risk criteria. Methods We used pooled cross-sectional data from three Cancer Control Modules (2005, 2010, 2015) of the National Health Interview Survey, a national in-person household interview survey. Eligible patients were adult females with a history of BC and/or OC meeting select 2017 National Comprehensive Cancer Network eligibility criteria on the basis of age of diagnosis and family history. Outcomes included the proportion of individuals reporting a history of discussing genetic testing with a health professional, being advised to undergo genetic testing, or undergoing genetic testing for BC or OC. Results Of 47,218 women, 2.7% had a BC history and 0.4% had an OC history. For BC, 35.6% met one or more select eligibility criteria; of those, 29.0% discussed, 20.2% were advised to undergo, and 15.3% underwent genetic testing. Testing rates for individual eligibility criteria ranged from 6.2% (relative with OC) to 18.2% (diagnosis ≤ 45 years of age). For OC, 15.1% discussed, 13.1% were advised to undergo, and 10.5% underwent testing. Using only four BC eligibility criteria and all patients with OC, an estimated 1.2 to 1.3 million individuals failed to receive testing. Conclusion Fewer than one in five individuals with a history of BC or OC meeting select National Cancer Comprehensive Network criteria have undergone genetic testing. Most have never discussed testing with a health care provider. Large national efforts are warranted to address this unmet need.

scholarly journals Adrenoleukodystrophy Newborn Screening in California Since 2016: Programmatic Outcomes and Follow-Up

2021 ◽  
Vol 7 (2) ◽  
pp. 22
Author(s):  
Jamie Matteson ◽  
Stanley Sciortino ◽  
Lisa Feuchtbaum ◽  
Tracey Bishop ◽  
Richard S. Olney ◽  
...  
Keyword(s):  
Newborn Screening ◽  
Program Implementation ◽  
Screening Program ◽  
Birth Prevalence ◽  
Variant Of Uncertain Significance ◽  
Implementation Challenges ◽  
Screening Programs ◽  
Uncertain Significance ◽  
Long Term Follow Up

X-linked adrenoleukodystrophy (ALD) is a recent addition to the Recommended Uniform Screening Panel, prompting many states to begin screening newborns for the disorder. We provide California’s experience with ALD newborn screening, highlighting the clinical and epidemiological outcomes observed as well as program implementation challenges. In this retrospective cohort study, we examine ALD newborn screening results and clinical outcomes for 1,854,631 newborns whose specimens were received by the California Genetic Disease Screening Program from 16 February 2016 through 15 February 2020. In the first four years of ALD newborn screening in California, 355 newborns screened positive for ALD, including 147 (41%) with an ABCD1 variant of uncertain significance (VUS) and 95 males diagnosed with ALD. After modifying cutoffs, we observed an ALD birth prevalence of 1 in 14,397 males. Long-term follow-up identified 14 males with signs of adrenal involvement. This study adds to a growing body of literature reporting on outcomes of newborn screening for ALD and offering a glimpse of what other large newborn screening programs can expect when adding ALD to their screening panel.

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