ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.1385A>G (p.Glu462Gly) (rs56403624)

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Total submissions: 23
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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) RCV000031319 SCV000244421 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 = 0.00000293
Invitae RCV000195299 SCV000071806 benign Hereditary breast and ovarian cancer syndrome 2020-11-26 criteria provided, single submitter clinical testing
GeneDx RCV000656588 SCV000210559 likely benign not provided 2021-05-19 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 10717622, 24504028, 15026808, 21952622, 21520273, 24323938, 19200354, 15172753, 20104584, 19491284, 18451181, 21990134, 17924331, 15695382, 19563646, 16905680, 27616075, 29036293, 32444794)
Ambry Genetics RCV000162999 SCV000213487 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.
Counsyl RCV000031319 SCV000220497 likely benign Breast-ovarian cancer, familial 2 2014-07-10 criteria provided, single submitter literature only
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000173630 SCV000224758 benign not specified 2014-10-13 criteria provided, single submitter clinical testing
Vantari Genetics RCV000162999 SCV000267014 benign Hereditary cancer-predisposing syndrome 2016-01-06 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000173630 SCV000301756 likely benign not specified criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000195299 SCV000494425 benign Hereditary breast and ovarian cancer syndrome 2015-08-20 criteria provided, single submitter clinical testing Variant Summary: The c.1385A>G variant involves the alteration of a non-conserved nucleotide and 2/5 in silico tools predict a benign outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.023%, primarily observed in the European (Non-Finnish) cohort at a frequency of 0.041%. These frequencies do not exceed the maximal expected allele frequency for a pathogenic variant in BRCA2 (0.075%). The variant was reported in the literature and databases in individuals who also have pathogenic BRCA1 (n=1) and BRCA2 (n=3) mutations (UMD, BIC, Simard_2007) suggesting a benign nature of the variant. Additionally, the variant was found to not segregate with disease in families tested (3 affected family members did not carry the variant; Gomez Garcia_2009). Functional studies showed the variant performed similarly to wild-type BRCA2 in assays of cellular survival and viability, homologous recombination repair, and genome instability (Wu_2005). Multiple reputable databases and clinical labs all classify the variant as benign/likely benign (Emory Genteics, UMD, ARUP, Ambry Genetics, SCRP, GeneDx, Counsyl) along with publications using multifactorial probability based models (Lindor_2012, Gomez Garcia_2009). All data, including co-segregation, functional assays, co-occurrence and the occurrence of this variant in the control population all support the classification of benign, therefore this variant has been classified as benign.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000173630 SCV000538483 uncertain significance 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: Multiple publications classify as VUS/not pathogenic; ExAC: 27/66408 European chromosomes
Color Health, Inc RCV000162999 SCV000683419 likely benign Hereditary cancer-predisposing syndrome 2015-02-05 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000031319 SCV000743259 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 RCV000031319 SCV000744410 benign Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Mendelics RCV000031319 SCV001138997 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000656588 SCV001148973 likely benign not provided 2018-11-01 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001642261 SCV001854675 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) RCV000031319 SCV000053924 benign Breast-ovarian cancer, familial 2 2006-09-07 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031319 SCV000145862 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000173630 SCV000591741 benign not specified no assertion criteria provided clinical testing The BRCA2 p.Glu462Gly variant was identified in 16 of 5462 proband chromosomes (frequency: 0.003) from individuals with breast or ovarian cancer and was absent in 200 control chromosomes from theses studies (Capanu 2011, Farrugia 2008, Hadjisavvas 2003, Hadjisavvas 2004, Simard 2007, van Harssel 2010); however, an insufficient number of controls were included in these studies to determine the frequency of this variant in the general population. The variant was also reported in HGMD, LOVD, UMD (14X as a neutral variant), and the BIC database (37X with unknown clinical importance). This variant was identified in dbSNP (ID: rs56403624) “With non-pathogenic allele”, and at a low frequency (0.0003) in the NHLBI Exome Sequencing Project. This residue is conserved in mammals but not in lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. Functional assays assessing cell survival, homologous recombination, centrosome regulation and nuclear localization have found no effect of the variant on normal BRCA2 function (Farrugia 2008, Wu 2005). In addition, five in silico studies predict this variant to be neutral or of little clinical significance (Capanu 2011 21520273, Easton 2007, Farrugia 2008, Lindor 2012, van Harssel 2010). This variant was not found to co-segregate with disease in an assessment of four families (Mohammadi 2009), and Simard (2007) found this variant co-occurring with a known deleterious mutation, increasing the likelihood that this variant does not have functional importance. Furthermore, Myriad classifies this variant as a polymorphism (personal communication). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Mayo Clinic Laboratories, Mayo Clinic RCV000656588 SCV000778645 benign not provided 2017-04-14 no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000173630 SCV001797651 benign not specified no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000173630 SCV001905801 benign not specified no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000173630 SCV001959985 benign not specified no assertion criteria provided clinical testing

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