ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2477C>A (p.Thr826Lys) (rs28897683)

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Total submissions: 20
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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) RCV000111873 SCV000244320 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 = 0.00000000203
Invitae RCV000047852 SCV000075865 benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
GeneDx RCV000173848 SCV000108657 benign not specified 2017-07-17 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.
CSER _CC_NCGL, University of Washington RCV000148407 SCV000190106 uncertain significance Breast neoplasm 2014-06-01 criteria provided, single submitter research Low GERP score may suggest that this variant may belong in a lower pathogenicity class
Ambry Genetics RCV000162503 SCV000212892 benign Hereditary cancer-predisposing syndrome 2014-11-18 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 RCV000111873 SCV000220408 likely benign Breast-ovarian cancer, familial 1 2014-06-12 criteria provided, single submitter literature only
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000173848 SCV000225009 benign not specified 2014-08-07 criteria provided, single submitter clinical testing
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000047852 SCV000267855 likely benign Hereditary breast and ovarian cancer syndrome 2016-04-25 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000173848 SCV000538444 uncertain significance not specified 2016-03-29 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: ExAC: 22/66720 European; ClinVar: 5 B/LB, 2 VUS
Department of Pathology and Molecular Medicine,Queen's University RCV000173848 SCV000588040 benign not specified 2017-04-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000679688 SCV000600289 benign not provided 2019-06-07 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162503 SCV000683039 likely benign Hereditary cancer-predisposing syndrome 2015-02-11 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000111873 SCV000746300 benign Breast-ovarian cancer, familial 1 2020-05-03 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679688 SCV000806919 likely benign not provided 2016-10-03 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000111873 SCV001283968 uncertain significance Breast-ovarian cancer, familial 1 2017-04-27 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170821 SCV001333439 likely benign Breast and/or ovarian cancer 2017-12-01 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000111873 SCV000053648 benign Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000111873 SCV000144452 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000173848 SCV000587223 benign not specified 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000111873 SCV000591390 likely benign Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing The BRCA1 p.Thr826Lys variant was identified in 12 of 6080 proband chromosomes (frequency: 0.002) from individuals or families with breast or ovarian cancer and was not identified in 372 control chromosomes from healthy individuals (Simard 2007, Capanu 2011, Tonin 1998, Palomba 2009, Klemp 2000, Dean 2015). The variant was identified in dbSNP (rs28897683) as “with other allele”, ClinVar (classified as benign by ENIGMA expert panel in 2015, Invitae, Ambry Genetics, Gene Dx and 6 other submitters; as likely benign by Counsyl, Color and 2 other submitters; and as uncertain significance by BIC and 3 other submitters), LOVD 3.0 (observed 17x) and UMD-LSDB (observed 33x). The variant was identified in control databases in 52 of 276616 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 4 of 24,028 chromosomes (freq: 0.0002), Latino in 8 of 34,412 chromosomes (freq: 0.0002) and European in 40 of 126,296 chromosomes (freq: 0.0003), while the variant was not observed in the Other, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The variant was observed in the UMD-LSDB database in 3 cases with co-occurring pathogenic variants: BRCA1 c.3669del (p.Cys1225Alafs*10), BRCA1 c.4251_4252del (p.Leu1418Argfs*9), and BRCA2 c.6359C>G (p.Ser2120*). In a complementation assay in BRCA1-deficient mouse embryonic stem cells, the variant was demonstrated to have no observed effect on cell proliferation and sensitivity to cisplatin, indicating the variant protein activity was sufficient to complement the BRCA1-null cells (Bouwman 2013). The p.Thr826 residue is conserved in mammals but not in more distantly related organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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 likely benign.

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