ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2077G>A (p.Asp693Asn) (rs4986850)

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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) RCV000111758 SCV000244313 benign Breast-ovarian cancer, familial 1 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 = 0.00000000000204. Also class 1 based on frequency >1% in an outbred sampleset. Frequency 0.01016 (African), 0.08443 (European), derived from 1000 genomes (2012-04-30).
Invitae RCV000047702 SCV000075715 benign Hereditary breast and ovarian cancer syndrome 2020-12-01 criteria provided, single submitter clinical testing
Counsyl RCV000111758 SCV000154007 benign Breast-ovarian cancer, familial 1 2014-01-02 criteria provided, single submitter literature only High frequency in a 1kG or ESP population: 7.0 %.
GeneDx RCV000157727 SCV000167248 benign Familial cancer of breast 2013-09-03 criteria provided, single submitter clinical testing The variant is found in BRCA1-BRCA2 panel(s).
Ambry Genetics RCV000129094 SCV000183805 benign Hereditary cancer-predisposing syndrome 2014-10-29 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.
Michigan Medical Genetics Laboratories,University of Michigan RCV000111758 SCV000195899 benign Breast-ovarian cancer, familial 1 2014-11-03 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000120289 SCV000202272 benign not specified 2015-03-25 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129094 SCV000292092 benign Hereditary cancer-predisposing syndrome 2014-11-05 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000120289 SCV000311787 benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000111758 SCV000403068 benign Breast-ovarian cancer, familial 1 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000047702 SCV000494306 benign Hereditary breast and ovarian cancer syndrome 2014-11-13 criteria provided, single submitter clinical testing
Baylor Genetics RCV000157727 SCV000540960 benign Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000120289 SCV000586880 benign not specified 2017-04-18 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282505 SCV000602670 benign none provided 2020-08-27 criteria provided, single submitter clinical testing
GeneKor MSA RCV000120289 SCV000693604 benign not specified 2017-11-01 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000111758 SCV000743421 benign Breast-ovarian cancer, familial 1 2014-10-09 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000111758 SCV000744666 benign Breast-ovarian cancer, familial 1 2015-09-21 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034730 SCV000043178 no known pathogenicity not provided 2012-07-13 no assertion criteria provided research Converted during submission to Benign.
ITMI RCV000120289 SCV000084441 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA1) RCV000111758 SCV000144288 benign Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing
Sharing Clinical Reports Project (SCRP) RCV000111758 SCV000189330 benign Breast-ovarian cancer, familial 1 2011-03-17 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000120289 SCV000591367 benign not specified no assertion criteria provided clinical testing The BRCA1 p.Asp693Asn variant was identified in the literature and was also identified in dbSNP (ID: rs4986850) “With Benign ,untested allele”, with a minor allele frequency of 0.034 (1000 Genomes Project), NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, LOVD, the ClinVar database (classified as a benign variant by the Sharing Clinical Reports Project, derived from Myriad reports, by Invitae, BIC, Counsy, GeneDX, Ambry Genetics and Biesecker Laboratory ), GeneInsight through the Canadian Open Genetics Repository (http://opengenetics.ca/) (1X, classified as “benign” by a clinical laboratory), the BIC database (64X with no clinical importance), and UMD (16X as a neutral variant). In UMD the variant was identified with a co-occurring pathogenic BRCA1 and BRCA2 variants (c.IVS22+5G>C (c.5406+5G>C); c.5503C>T (p.Arg1835X); c.3257T>G (p.Leu1086X) BRCA1 and c.6405_6409delCTTAA (p.Asn2135LysfsX3) BRCA2), increasing the likelihood that the p.Asp693Asn variant does not have clinical significance. This variant was also identified in the HAPMAP-CEU in 22 of 226 chromosomes (frequency: 0.097), HAPMAP-YRI in 2 of 226 chromosomes (frequency: 0.009), HAPMAP-MKK in 5 of 286 chromosomes (frequency: 0.017), Exome Variant Server project in 706 of 13004 European American and African American alleles, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin.The p.Asp693 residue is not conserved in mammals 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. Furthermore, six studies call the variant as polymorphism, neutral or of little clinical significance (Abkevich 2004, Bodian 2014, Feliubadalo 2013, Johnston 2012, Lindor 2012, Tavtigian 2006). 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 RCV000111758 SCV000733649 benign Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000034730 SCV000778763 benign not provided 2016-12-27 no assertion criteria provided clinical testing
True Health Diagnostics RCV000129094 SCV000787895 benign Hereditary cancer-predisposing syndrome 2018-02-20 no assertion criteria provided clinical testing

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