ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.7150C>A (p.Gln2384Lys) (rs55977008)

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Total submissions: 25
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031668 SCV000244499 benign Breast-ovarian cancer, familial 2 2015-08-10 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000000334
Invitae RCV000045149 SCV000073162 benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
Counsyl RCV000031668 SCV000154090 likely benign Breast-ovarian cancer, familial 2 2014-03-20 criteria provided, single submitter literature only
CSER _CC_NCGL, University of Washington RCV000148435 SCV000190134 likely benign Breast neoplasm 2014-06-01 criteria provided, single submitter research
Michigan Medical Genetics Laboratories,University of Michigan RCV000031668 SCV000196002 benign Breast-ovarian cancer, familial 2 2014-11-03 criteria provided, single submitter clinical testing
GeneDx RCV000120353 SCV000210646 benign not specified 2015-11-25 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000162557 SCV000212967 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Pathway Genomics RCV000031668 SCV000223772 likely benign Breast-ovarian cancer, familial 2 2014-10-30 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000120353 SCV000225993 benign not specified 2014-12-11 criteria provided, single submitter clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000045149 SCV000267845 likely benign Hereditary breast and ovarian cancer syndrome 2017-02-14 criteria provided, single submitter clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000045149 SCV000296859 likely benign Hereditary breast and ovarian cancer syndrome 2015-11-30 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000404007 SCV000383760 likely benign Fanconi anemia, complementation group D1 2018-01-23 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000031668 SCV000383761 likely benign Breast-ovarian cancer, familial 2 2018-01-23 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000120353 SCV000538475 likely benign not specified 2016-03-28 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.5% (49/10380) African; ClinVar: 6 B/LB, 2 VUS
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282691 SCV000602841 benign none provided 2019-10-15 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162557 SCV000910606 benign Hereditary cancer-predisposing syndrome 2015-09-30 criteria provided, single submitter clinical testing
Mendelics RCV000031668 SCV001139172 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001642440 SCV001854915 benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000031668 SCV000054275 benign Breast-ovarian cancer, familial 2 2007-02-13 no assertion criteria provided clinical testing
ITMI RCV000120353 SCV000084505 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA2) RCV000031668 SCV000147029 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000656615 SCV000778703 likely benign not provided 2017-05-19 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735602 SCV000863740 benign Breast and/or ovarian cancer no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357853 SCV001553442 benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Gln2384Lys variant was identified in 3 of 4340 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer and was not identified in 280 control chromosomes from healthy individuals (Fackenthal 2005, Gao 2000, Borg 2010). The variant was also identified in dbSNP (ID: rs55977008) “With other allele”, with a minor allele frequency of 0.001 (1000 Genomes Project), and the NHLBI Exome Sequencing Project (Exome Variant Server) in 24 of 4406 African American (frequency 0.005) and 0 of 8600 European American alleles; this variant was identified in the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) 49 of 10380 African, 2 of 11578 latino and 1 of "other" individuals and it was not found in European, European (Non-Finnish), South Asian and East Asian individuals, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The variant was also identified in GeneInsight as unclassified by a clinical laboratory within the Canadian Open Genetics Repository, HGMD, LOVD (predicted neutral, non-pathogenic or of no clinical significance), the BIC database (31X with unknown clinical importance and UMD (6X as a neutral variant and also found co-occurring with silent variant, c.4071A>C (p.Leu1357Leu). The variant was submitted to the ClinVar database by multiple submitters: classified as benign variant by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports) and Ambry Genetics; uncertain significance by BIC and likely benign by Counsyl and by Invitae; classification was not provided by ITMI. The p.Gln2384 residue is not conserved in mammals and lower organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The p.Gln2384Lys variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant was also identified with high frequency in Algerian and African American breast cancer patients with family history, and BRCA1/2 mutation negative (Cherbal 2012, Nanda 2005). Using a posterior probablility model based on several sources of information for the purpose of VUS classification, the variant was classified as not pathogenic (Lindor 2011). In addition, the variant was found in a patient with uterine serous carcinoma but was not considered a deleterious mutation (Pennington 2013). The variant was identified with a co-occurring BRCA1 pathogenic variant in an individual tested by our lab, increasing the likelihood that this variant is benign. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as benign.
Human Genetics - Radboudumc,Radboudumc RCV000120353 SCV001955882 benign not specified no assertion criteria provided clinical testing

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