ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4357+1G>A (rs80358027)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 16
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131879 SCV000186934 pathogenic Hereditary cancer-predisposing syndrome 2017-06-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity,Functionally-validated splicing mutation,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Breast Cancer Information Core (BIC) (BRCA1) RCV000031165 SCV000145068 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Color RCV000131879 SCV000688488 pathogenic Hereditary cancer-predisposing syndrome 2016-04-20 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031165 SCV000325930 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031165 SCV000488708 pathogenic Breast-ovarian cancer, familial 1 2016-05-25 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000167804 SCV000591509 pathogenic Hereditary breast and ovarian cancer syndrome criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031165 SCV000244360 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 = 0.9999
GeneDx RCV000048532 SCV000210176 pathogenic not provided 2018-11-12 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.4357+1G>A or IVS12+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 12 of the BRCA1 gene. Splicing assays have demonstrated that this variant, also defined as BRCA1 4476+1G>A or IVS13+1G>A using alternate nomenclature, results in skipping of exon 12, also denoted exon 13 by alternate nomenclature (Thomassen 2012). This disruption would be predicted to lead to an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. BRCA1 c.4357+1G>A has been reported in association with early onset breast cancer and hereditary breast/ovarian cancer (Pal 2004, Thomassen 2012, Couch 2015, Lynce 2015, Pal 2015, Alemar 2016, Frey 2017, Delgado-Balderas 2018, Isaacsson 2018). Additionally, this variant was strongly predicted by Lindor et al. (2012) to be pathogenic based on tumor pathology, clinical histories, family studies and co-occurrence with deleterious variants, and is described as a recurrent pathogenic variant in individuals of African ancestry (Hall 2009, Donenberg 2011). Based on the current evidence, we consider BRCA1 c.4357+1G>A to be pathogenic.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000031165 SCV000839903 pathogenic Breast-ovarian cancer, familial 1 2017-07-31 criteria provided, single submitter clinical testing This c. 4357+1G>A (also known as IVS13+1G>A) variant in the BRCA1 gene has been reported in multiple patients with breast cancer from two families breast cancer patients (PMID15533909, PMID21769658). In the first family, The first patientthe proband was diagnosed at 30 years of age and with three female relatives of the proband were diagnosed with breast cancer before age 40 (PMID 5533909). The second patient in the second family was diagnosed at 26 years of age without with no known family history (PMID21769658). In silico analysis and experimental studies suggest that this variant causes exon 13 skipping (PMID24667779,21735045, 21769658). A multifactorial likelihood algorithm also predicts this variant to be deleterious (PMID 17924331). Based on the current evidence, this c. 4357+1G>A variant in the BRCA1 gene is classified as pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000167804 SCV000699137 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-27 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.4357+1G>A variant involves the alteration of a conserved intronic nucleotide located at the canonical splicing site. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict that this variant abolishes the 5' splicing donor site. These predictions have been confirmed by RT-PCR showing that it leads to skipping of exon 12 (legacy exon 13) and frameshift p.Arg1397TyrfsX2 (Thomassen_2011). This variant was found in 1/121252 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). It has also been reported in multiple HBOC patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000167804 SCV000076545 pathogenic Hereditary breast and ovarian cancer syndrome 2018-11-13 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 12 of the BRCA1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs80358027, ExAC 0.02%). This variant has been reported in individuals with breast cancer (PMID: 15533909, 20104584, 24013928, 25085752, 25452441, 26681312, 24797986). This variant is also known as IVS13+1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 37584). Based on a multifactorial likelihood algorithm using genetic, in silico, and statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 17924331, 21990134, 25085752). Experimental studies have shown that this variant affects BRCA1 RNA splicing, causing exon 12 skipping (also referred as exon 13 skipping in the literature) (PMID: 24667779, 21735045, 21769658). 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). For these reasons, this variant has been classified as Pathogenic.
Michigan Medical Genetics Laboratories,University of Michigan RCV000031165 SCV000267711 pathogenic Breast-ovarian cancer, familial 1 2016-04-21 criteria provided, single submitter clinical testing
Pathway Genomics RCV000031165 SCV000223751 pathogenic Breast-ovarian cancer, familial 1 2014-10-30 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000048532 SCV000296293 pathogenic not provided 2015-02-12 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000167804 SCV000587392 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000031165 SCV000053765 pathogenic Breast-ovarian cancer, familial 1 2012-10-18 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.