ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2458A>G (p.Lys820Glu) (rs56082113)

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Total submissions: 24
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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) RCV000111865 SCV000244319 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 0.06098 (African), derived from 1000 genomes (2012-04-30).
Invitae RCV000047846 SCV000075859 benign Hereditary breast and ovarian cancer syndrome 2020-12-08 criteria provided, single submitter clinical testing
Counsyl RCV000111865 SCV000154020 benign Breast-ovarian cancer, familial 1 2014-02-14 criteria provided, single submitter literature only
Michigan Medical Genetics Laboratories,University of Michigan RCV000111865 SCV000195905 benign Breast-ovarian cancer, familial 1 2014-11-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000162590 SCV000213007 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Co-occurence with mutation in same gene (phase unknown);General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;In silico models in agreement (benign);Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000120273 SCV000225004 benign not specified 2014-07-01 criteria provided, single submitter clinical testing
Vantari Genetics RCV000162590 SCV000267009 likely benign Hereditary cancer-predisposing syndrome 2016-01-05 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162590 SCV000292127 benign Hereditary cancer-predisposing syndrome 2014-12-06 criteria provided, single submitter clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000120273 SCV000297224 benign not specified 2015-07-27 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000120273 SCV000311790 benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000111865 SCV000403065 benign Breast-ovarian cancer, familial 1 2018-01-13 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 RCV000047846 SCV000494356 benign Hereditary breast and ovarian cancer syndrome 2014-02-12 criteria provided, single submitter clinical testing
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000047846 SCV000576443 likely benign Hereditary breast and ovarian cancer syndrome 2017-02-14 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001281783 SCV000602692 benign none provided 2020-06-23 criteria provided, single submitter clinical testing
GeneKor MSA RCV000120273 SCV000693607 benign not specified 2017-11-01 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000111865 SCV000744656 benign Breast-ovarian cancer, familial 1 2015-09-21 criteria provided, single submitter clinical testing
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000162590 SCV000803151 likely benign Hereditary cancer-predisposing syndrome 2018-05-23 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034732 SCV000043176 no known pathogenicity not provided 2012-07-13 no assertion criteria provided research Converted during submission to Benign.
ITMI RCV000120273 SCV000084425 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA1) RCV000111865 SCV000144442 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Pathway Genomics RCV000111865 SCV000187729 likely benign Breast-ovarian cancer, familial 1 2014-07-24 no assertion criteria provided literature only
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000120273 SCV000591389 benign not specified no assertion criteria provided clinical testing The p.Lys820Glu variant has been identified in 7 of 4428 proband chromosomes (frequency 0.002) in individuals with breast or ovarian cancers (Capanu 2011, Fackenthal 2005, Jalkh 2012); however control chromosomes from healthy individuals were not included in these studies. This variant was identified in dbSNP (rs56082113) and with a frequency of 3% in the African American population from the Exome Variant Server. The variant was also reported 30x in BIC as a variant of unknown clinical importance, and 10x in the UMD as a neutral variant which co-occurred with a known BRCA1 pathogenic mutation (c.3607C>T (p.Arg1203X)). The p.Lys820 residue is not conserved in evolution and the variant amino acid (Glu) is present in macaque and opossum. Furthermore, computational analyses (PolyPhen2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein, and two in silico studies have concluded this variant to be neutral or of little clinical significance (Lindor 2012, Tavtigian 2006); however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as benign.
Mayo Clinic Laboratories, Mayo Clinic RCV000034732 SCV000778756 likely benign not provided 2018-02-19 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735498 SCV000863636 benign Breast and/or ovarian cancer 2013-04-23 no assertion criteria provided clinical testing

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