ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.7544C>T (p.Thr2515Ile) (rs28897744)

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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) RCV000031684 SCV000244473 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 = 0.0000643
Invitae RCV000045242 SCV000073255 benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
Counsyl RCV000031684 SCV000154099 likely benign Breast-ovarian cancer, familial 2 2014-04-08 criteria provided, single submitter literature only
GeneDx RCV000034460 SCV000210655 likely benign not provided 2020-09-17 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 21990134, 24728327, 28288110, 28324225, 24082139, 30611917, 25556971, 18844490, 19043619, 9971877, 12955719, 12955716, 12161607, 25782689, 23884293, 10978364, 17250666, 22703879, 21702907, 24323938, 15695382, 27376475, 28263838, 27153395, 29061375, 28866612, 28283652, 26517685, 30696104, 29988080, 31131559, 32444794, 29884841)
Ambry Genetics RCV000162697 SCV000213152 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s);Subpopulation frequency in support of benign classification
Illumina Clinical Services Laboratory,Illumina RCV000271965 SCV000383769 likely benign Fanconi anemia, complementation group D1 2019-10-08 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 RCV000031684 SCV000383770 likely benign Breast-ovarian cancer, familial 2 2019-10-08 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.
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000120358 SCV000586975 benign not specified 2017-04-18 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000120358 SCV000605777 uncertain significance not specified 2016-06-16 criteria provided, single submitter clinical testing Disclaimer: This variant has not undergone full assessment. The following are pr eliminary notes: ClinVar: 7 labs classify as B/LB
Color Health, Inc RCV000162697 SCV000683887 likely benign Hereditary cancer-predisposing syndrome 2014-12-16 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000031684 SCV000744520 benign Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000162697 SCV000803157 likely benign Hereditary cancer-predisposing syndrome 2018-05-23 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000034460 SCV000805765 likely benign not provided 2017-07-27 criteria provided, single submitter clinical testing
Mendelics RCV000045242 SCV000838855 likely benign Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000034460 SCV000885105 benign not provided 2017-11-17 criteria provided, single submitter clinical testing
Mendelics RCV000031684 SCV001139185 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001642450 SCV001854934 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
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034460 SCV000043227 probably not pathogenic not provided 2012-07-13 no assertion criteria provided research Converted during submission to Likely benign.
Sharing Clinical Reports Project (SCRP) RCV000031684 SCV000054291 benign Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
ITMI RCV000120358 SCV000084510 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA2) RCV000031684 SCV000147118 benign Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000120358 SCV000592122 benign not specified no assertion criteria provided clinical testing The BRCA2 p.Thr2515Ile variant was identified in 4 of 3460 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer (Campos 2001, Diez 2003, Plaschke 2000, Meindl 2002), and was present in 3 of 830 control chromosomes (frequency: 0.004) from healthy individuals (Cvok 2008, Meindl 2002). The variant was also identified in several database searches, including: GeneInsight – COGR (submitted by a clinical laboratory as “unclassified”), UMD/BRCA Share (37X with a “likely neutral” classification), ARUP Laboratories BRCA Mutation Database (classified as “not pathogenic or of no clinical significance”), BIC (72X as a variant with no clinical significance), LOVD – IARC (classified as “not pathogenic or of no clinical significance”), and ClinVar (classified as “benign” by four submitters and “likely benign” by three submitters). In the UMD/BRCA Share database, three samples were listed with co-occurring pathogenic BRCA1 or BRCA2 variants, increasing the likelihood that the p.Thr2515Ile variant is not clinically significant. In addition, the variant was identified at polymorphic frequencies in three HAPMAP populations (HAPMAP-MEX (Mexican), HAPMAP-JPT (Japanese), HAPMAP-HCB (Han Chinese)) listed in dbSNP (ID: rs28897744), and Myriad classifies this variant as a polymorphism (personal communication). The p.Thr2515 residue is not conserved across mammals and other organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. One study utilizing in vitro assays suggests that the variant may impact certain BRCA2 functions and cellular localization; however, segregation analysis of nine pedigrees in this same study found low odds in favour of disease causality (Wu 2005). Two multifactorial analysis studies and one bioinformatics study predict the variant to be neutral or have no clinical significance (Karchin 2008, Lindor 2012, Spurdle 2008). The 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. In addition, RNA analysis done in a study by Campos (2003) found that the variant did not alter splicing. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000031684 SCV000733300 benign Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000120358 SCV001905992 benign not specified no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000120358 SCV001955935 benign not specified no assertion criteria provided clinical testing

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