Submissions for variant NM_000059.4(BRCA2):c.9976A>T (p.Lys3326Ter) (rs11571833)

Total submissions: 39

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031849	SCV000244498	benign	Breast-ovarian cancer, familial 2	2016-02-16	reviewed by expert panel	curation	Case-control and frequency data indicate that K3326X does not confer a high risk of cancer (OR 1.3-1.5, dependent on breast or ovarian cancer subtype).
Invitae	RCV000045926	SCV000073939	benign	Hereditary breast and ovarian cancer syndrome	2019-12-31	criteria provided, single submitter	clinical testing
Counsyl	RCV000031849	SCV000154053	benign	Breast-ovarian cancer, familial 2	2014-01-02	criteria provided, single submitter	literature only
Ambry Genetics	RCV000128910	SCV000172777	benign	Hereditary cancer-predisposing syndrome	2014-11-19	criteria provided, single submitter	clinical testing	Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Co-occurence with mutation in same gene (phase unknown);General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;Intact protein function observed in appropriate functional assay(s);Other strong data supporting benign classification;Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
Michigan Medical Genetics Laboratories,University of Michigan	RCV000031849	SCV000196031	benign	Breast-ovarian cancer, familial 2	2014-11-03	criteria provided, single submitter	clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000120374	SCV000202309	benign	not specified	2015-10-13	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000045926	SCV000212199	benign	Hereditary breast and ovarian cancer syndrome	2015-03-11	criteria provided, single submitter	research
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario	RCV000735635	SCV000219429	likely benign	Breast and/or ovarian cancer	2017-12-19	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia	RCV000045926	SCV000257622	benign	Hereditary breast and ovarian cancer syndrome	2015-07-09	criteria provided, single submitter	clinical testing
Color Health, Inc	RCV000128910	SCV000292115	benign	Hereditary cancer-predisposing syndrome	2014-11-19	criteria provided, single submitter	clinical testing
PreventionGenetics,PreventionGenetics	RCV000120374	SCV000301783	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000031849	SCV000383808	likely benign	Breast-ovarian cancer, familial 2	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics	RCV000034474	SCV000511377	benign	not provided	2016-12-27	criteria provided, single submitter	clinical testing
Fulgent Genetics,Fulgent Genetics	RCV000031849	SCV000575759	benign	Breast-ovarian cancer, familial 2	2016-02-22	criteria provided, single submitter	clinical testing
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency	RCV000120374	SCV000586993	benign	not specified	2017-04-18	criteria provided, single submitter	clinical testing
Department of Pathology and Molecular Medicine,Queen's University	RCV000120374	SCV000588130	benign	not specified	2017-04-20	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000120374	SCV000592309	likely benign	not specified	2015-11-30	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV001283531	SCV000602758	benign	none provided	2020-08-07	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000120374	SCV000693648	benign	not specified	2017-11-01	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000034474	SCV000695284	benign	not provided	2016-08-12	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.9976A>T (p.Lys3326X) variant results in a termination codon at the penultimate exon, predicted to cause a truncation of the last 93 amino acids. This variant is not expected to affect any known domain (InterPro) and no truncations downstream of this position have been reported to be pathogenic in literature and databases. This variant was found in 2327/296226 control chromosomes (including 8 homozygotes) at a frequency of 0.0078555, which is approximately 10 times the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503), suggesting this variant is likely a benign polymorphism. In addition, several clinical diagnostic laboratories/reputable databases have classified this variant as benign (14)/likely benign (1). Available family, co-occurrence and functional data also show that it is not a disease causing variant. Despite these, this variant is found at considerably high frequency, especially in patients with breast and/or ovarian cancer, raising a possibilty that it may be a risk variant. Using weighted logistic regression, Meeks et al 2016 analyzed data from the large iCOGS study including 76637 cancer case patients and 83796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Other adjustments in the study were adjustment for attained age, consortium study site, and principal components of population structure. From the study, weighted ORs for invasive breast cancer and ovarian cancers were 1.28 (confidence interval 1.17-1.4; P-value=3.84x10e-3) and 1.26 (confidence interval 1.1-1.43; P-value=3.84x10e-3), respectively. The authors conclude that this study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Hence this variant is a risk allele which attributes a significant but a low risk in development of breast or ovarian cancer. In addition, other genetic/lifestyle/environmental factors may also be playing a part in elevation of risk. Taken together, this variant is classified as Benign for HBOC.
Genome Diagnostics Laboratory,University Medical Center Utrecht	RCV000031849	SCV000743529	benign	Breast-ovarian cancer, familial 2	2014-10-09	criteria provided, single submitter	clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center	RCV000031849	SCV000744794	benign	Breast-ovarian cancer, familial 2	2015-09-21	criteria provided, single submitter	clinical testing
Mendelics	RCV000031849	SCV001139281	benign	Breast-ovarian cancer, familial 2	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000034474	SCV001149001	likely benign	not provided	2018-06-01	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV001112896	SCV001270610	likely benign	Fanconi anemia, complementation group D1	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000031849	SCV001429528	uncertain significance	Breast-ovarian cancer, familial 2	2017-09-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000120374	SCV001469470	benign	not specified	2020-05-11	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health	RCV000034474	SCV000043239	no known pathogenicity	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Benign.
Sharing Clinical Reports Project (SCRP)	RCV000031849	SCV000054457	benign	Breast-ovarian cancer, familial 2	2012-05-01	no assertion criteria provided	clinical testing
ITMI	RCV000120374	SCV000084526	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031849	SCV000145737	benign	Breast-ovarian cancer, familial 2	2002-05-29	no assertion criteria provided	clinical testing
Pathway Genomics	RCV000031849	SCV000187732	likely benign	Breast-ovarian cancer, familial 2	2014-07-24	no assertion criteria provided	literature only
GeneReviews	RCV000031849	SCV000484958	pathogenic	Breast-ovarian cancer, familial 2	2016-12-15	no assertion criteria provided	literature only
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto	RCV000120374	SCV000588018	benign	not specified	2014-01-31	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen	RCV000031849	SCV000733342	benign	Breast-ovarian cancer, familial 2		no assertion criteria provided	clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic	RCV000034474	SCV000778727	likely benign	not provided	2017-02-02	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000128910	SCV000787962	benign	Hereditary cancer-predisposing syndrome	2018-02-20	no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735635	SCV000863773	likely benign	Breast and/or ovarian cancer	2013-08-02	no assertion criteria provided	clinical testing
Center of Medical Genetics and Primary Health Care	RCV001004846	SCV000987251	benign	Malignant tumor of breast	2020-04-08	no assertion criteria provided	research	ACMG Guidelines 2015 criteria