ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.4258G>T (p.Asp1420Tyr) (rs28897727)

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Total submissions: 36
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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) RCV000083103 SCV000244448 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 = 0.000102
Invitae RCV000044377 SCV000072390 benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
Counsyl RCV000083103 SCV000154044 likely benign Breast-ovarian cancer, familial 2 2014-01-02 criteria provided, single submitter literature only
GeneDx RCV000120339 SCV000167364 benign not specified 2013-10-09 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.
Michigan Medical Genetics Laboratories,University of Michigan RCV000083103 SCV000195982 benign Breast-ovarian cancer, familial 2 2014-11-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000162541 SCV000212944 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.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000735549 SCV000219337 benign Breast and/or ovarian cancer 2016-01-06 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000120339 SCV000225172 benign not specified 2014-11-12 criteria provided, single submitter clinical testing
Vantari Genetics RCV000162541 SCV000267017 likely benign Hereditary cancer-predisposing syndrome 2016-02-04 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162541 SCV000292117 benign Hereditary cancer-predisposing syndrome 2015-03-05 criteria provided, single submitter clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000044377 SCV000296855 benign Hereditary breast and ovarian cancer syndrome 2015-08-24 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000083103 SCV000383697 likely benign Breast-ovarian cancer, familial 2 2018-02-12 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000044377 SCV000494324 benign Hereditary breast and ovarian cancer syndrome 2014-04-07 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000034440 SCV000510802 likely benign not provided 2017-01-24 criteria provided, single submitter clinical testing Converted during submission to Likely benign.
Fulgent Genetics,Fulgent Genetics RCV000083103 SCV000575731 likely benign Breast-ovarian cancer, familial 2 2015-08-26 criteria provided, single submitter clinical testing
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000120339 SCV000586948 benign not specified 2017-04-18 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283158 SCV000602780 benign none provided 2020-08-20 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034440 SCV000692771 likely benign not provided 2018-05-01 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000083103 SCV000743297 benign Breast-ovarian cancer, familial 2 2014-10-09 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000083103 SCV000744454 benign Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000120339 SCV000805705 benign not specified 2017-06-20 criteria provided, single submitter clinical testing
Mendelics RCV000083103 SCV001139086 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001642542 SCV001854793 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 RCV000034440 SCV000043208 no known pathogenicity not provided 2012-07-13 no assertion criteria provided research Converted during submission to Benign.
ITMI RCV000120339 SCV000084491 not provided not specified 2013-09-19 no assertion provided reference population
Sharing Clinical Reports Project (SCRP) RCV000083103 SCV000115177 benign Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000083103 SCV000146395 not provided Breast-ovarian cancer, familial 2 no assertion provided clinical testing
Pathway Genomics RCV000083103 SCV000187734 likely benign Breast-ovarian cancer, familial 2 2014-07-24 no assertion criteria provided literature only
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353826 SCV000591897 benign Malignant tumor of breast no assertion criteria provided clinical testing The p.Asp1420Tyr variant has been previously reported in the literature in 203 of 18968 proband chromosomes (frequency of 0.011) with breast and ovarian cancer, and was also identified in 109 of 8530 (frequency of 0.013) control chromosomes increasing the likelihood that this is a low frequency benign variant It is listed in dbSNP database as coming from a "clinical source" (ID#: rs28897727) with a global minor allele frequency (MAF) of 0.001/2, and has an average heterozygosity of 0.008+/-0.062, increasing the likelihood that it is a benign variant. The Asp1420 residue is not highly conserved in mammals and computational analyses (PolyPhen2, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein. However, this information is not predictive enough to rule out pathogenicity. Functional studies have shown that compared to the wild-type protein, the p.Asp1420Tyr variant showed similar repair capacity and protein interactions, particularly with RAD51 (Davies_2001_11239456, Galkin_2005_15937124, Kuznetsov_2008_18607349). In addition, in two studies, one of which was a case control study, the allele frequency was higher in controls compared to the proband (Dombernowsky_2009_19661094, Stuppia_2003_12872265), thereby increasing the likelihood that this variant does not have clinical significance. Myriad genetics classifies this variant as a polymorphism, increasing the likelihood this variant is benign. In summary, we cannot rule out the possibility that this variant may contribute to the phenotype in these individuals, but based on the above information this variant is classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000083103 SCV000733255 benign Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000034440 SCV000778674 benign not provided 2016-12-12 no assertion criteria provided clinical testing
True Health Diagnostics RCV000162541 SCV000787930 benign Hereditary cancer-predisposing syndrome 2018-01-05 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735549 SCV000863687 likely pathogenic Breast and/or ovarian cancer 2008-03-29 no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000120339 SCV001797615 benign not specified no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000120339 SCV001906316 benign not specified no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000120339 SCV001958459 benign not specified no assertion criteria provided clinical testing

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