ClinVar Miner

Submissions for variant NM_007299.4(BRCA1):c.1965+1G>A (rs80358150)

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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) RCV000031235 SCV000244394 pathogenic 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 5 based on posterior probability = 1
Invitae RCV000074601 SCV000076909 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-17 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 19 of the BRCA1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several families with breast or ovarian cancer (PMID: 11149413, 19949876, 16683254). ClinVar contains an entry for this variant (Variation ID: 37654). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). Multifactorial likelihood analysis also predicts this variant to be damaging (PMID: 21990134, 17924331), which is supported by a mini-gene splicing assay, which demonstrates the skipping of exon 20 (PMID: 24667779). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000235135 SCV000108686 pathogenic not provided 2018-09-14 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.5277+1G>A or IVS19+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 19 of the BRCA1 gene. The variant destroys a canonical splice donor site and has been proven through functional studies to cause exonic skipping, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product (Tesoriero 2005, Sanz 2010, Steffensen 2014). This variant, also known as BRCA1 5396+1G>A or IVS20+1G>A using alternate nomenclature, has been reported in individuals with early-onset or familial breast and/or ovarian cancer (de la Hoya 2001, Diez 2003, van Harssel 2010, Lara 2012). Based on the current evidence, we consider this variant to be pathogenic.
Ambry Genetics RCV000131865 SCV000186920 pathogenic Hereditary cancer-predisposing syndrome 2016-12-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting pathogenic classification,Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity,Functionally-validated splicing mutation
Counsyl RCV000031235 SCV000220602 pathogenic Breast-ovarian cancer, familial 1 2014-08-19 criteria provided, single submitter literature only
Color RCV000131865 SCV000292160 pathogenic Hereditary cancer-predisposing syndrome 2015-01-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235135 SCV000296332 pathogenic not provided 2015-07-01 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031235 SCV000326234 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000074601 SCV000591605 pathogenic Hereditary breast and ovarian cancer syndrome 2013-06-12 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000507129 SCV000602686 pathogenic not specified 2017-05-24 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000074601 SCV000699231 pathogenic Hereditary breast and ovarian cancer syndrome 2016-05-16 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.5277+1G>A variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict the complete loss of a splice donor site, and experimental studies have confirmed an impact on normal splicing (Tesoriero_2005). This variant is absent in 121412 control chromosomes but has been found in numerous affected individuals in the literature and databases. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000031235 SCV000743373 pathogenic Breast-ovarian cancer, familial 1 2014-10-08 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000031235 SCV000744588 pathogenic Breast-ovarian cancer, familial 1 2015-09-21 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031235 SCV000053836 pathogenic Breast-ovarian cancer, familial 1 2012-05-02 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031235 SCV000145422 pathogenic Breast-ovarian cancer, familial 1 1999-12-30 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000074601 SCV000587485 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000031235 SCV000733590 pathogenic Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing
True Health Diagnostics RCV000131865 SCV000787910 pathogenic Hereditary cancer-predisposing syndrome 2017-10-30 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735562 SCV000863700 pathogenic Breast and/or ovarian cancer 2016-01-22 no assertion criteria provided clinical testing
MutSpliceDB: a database of splice sites variants effects on splicing,NIH RCV000235135 SCV000925675 not provided not provided no assertion provided in vitro

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