ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4357+1G>A

gnomAD frequency: 0.00001  dbSNP: rs80358027
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Total submissions: 22
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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) RCV000031165 SCV000244360 pathogenic Breast-ovarian cancer, familial, susceptibility to, 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
Invitae RCV000167804 SCV000076545 pathogenic Hereditary breast ovarian cancer syndrome 2023-12-01 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 12 of the BRCA1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs80358027, gnomAD 0.004%). Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 15533909, 20104584, 24013928, 24797986, 25085752, 25452441, 26681312). This variant is also known as IVS13+1G>A. ClinVar contains an entry for this variant (Variation ID: 37584). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 17924331). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 21735045, 21769658, 24667779; Invitae). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000131879 SCV000186934 pathogenic Hereditary cancer-predisposing syndrome 2021-07-22 criteria provided, single submitter clinical testing The c.4357+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 11 of the BRCA1 gene. This mutation has been reported in multiple individuals with personal and/or family history consistent with hereditary breast and ovarian cancer (HBOC) syndrome (Pal T et al. Cancer Epidemiol. Biomarkers Prev. 2004 Nov;13(11 Pt 1):1794-9; Akbari MR et al. Clin. Genet. 2014 Jan;85:64-7; Tihomirova L et al. Adv Med Sci, 2014 Mar;59:114-9; Couch FJ et al. J. Clin. Oncol., 2015 Feb;33:304-11; Alemar B et al. Cancer Genet. 2016 Sep;209:417-422; Rebbeck TR et al. Hum. Mutat., 2018 May;39:593-620). Functional analyses have demonstrated that this alteration leads to a skipping of coding exon 11 (also known as exon 13), causing a frameshift and alternate stop codon (Ambry internal data; Thomassen M et al. Breast Cancer Res. Treat. 2012 Apr;132:1009-23). In addition, this alteration has been classified as pathogenic (p>0.99) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence (Easton DF et al. Am. J. Hum. Genet. 2007 Nov;81:873-83; Lindor NM et al. Hum. Mutat. 2012 Jan;33:8-21; Vallee MP et al. Hum. Mutat. 2012 Jan;33:22-8). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
GeneDx RCV000048532 SCV000210176 pathogenic not provided 2022-06-20 criteria provided, single submitter clinical testing Canonical splice site variant demonstrated to result skipping of exon 12 which is predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease (Thomassen 2012, Steffensen 2014); Observed in individuals with BRCA1-related cancers (Pal 2004, Thomassen 2012, Couch 2015, Pal 2015, Alemar 2016, Frey 2017, Delgado-Balderas 2018, Isaacsson Velho 2018); Multifactorial studies suggest this variant is associated with breast and ovarian cancer (Easton 2007, Lindor 2012); Classified as pathogenic by a well-established clinical consortium and/or database (ClinVar); Also known as 4476+1G>A (IVS13+1G>A); This variant is associated with the following publications: (PMID: 17924331, 30787465, 21735045, 15533909, 26287763, 24013928, 24797986, 20838878, 19241424, 25920394, 27425403, 25085752, 25525159, 28495237, 28476184, 25452441, 20104584, 26295337, 29368341, 28918466, 29997359, 26681312, 29907814, 30702160, 29446198, 30720243, 30322717, 21769658, 24667779, 33646313, 31447099, 31825140, 21990134)
Pathway Genomics RCV000031165 SCV000223751 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2014-10-30 criteria provided, single submitter clinical testing
Michigan Medical Genetics Laboratories, University of Michigan RCV000031165 SCV000267711 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2016-04-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000048532 SCV000296293 pathogenic not provided 2020-06-01 criteria provided, single submitter clinical testing The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031165 SCV000325930 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031165 SCV000488708 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2016-05-25 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000131879 SCV000688488 pathogenic Hereditary cancer-predisposing syndrome 2022-06-13 criteria provided, single submitter clinical testing This variant causes a G to A nucleotide substitution at the +1 position of intron 12 of the BRCA1 gene. RNA studies have reported this variant to cause the out-of-frame skipping of exon 12 in carrier RNA and in minigene splicing assay (PMID: 21769658, 24667779 ), resulting in an unstable mRNA transcript (PMID: 21769658). This variant has been observed in multiple individuals and families affected with breast and ovarian cancer (PMID: 15533909, 20104584, 21769658, 23458327, 24797986, 25452441, 27425403, 30322717) and prostate cancer (PMID: 29368341). This variant has been identified in 1/251154 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000167804 SCV000699137 pathogenic Hereditary breast 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.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000031165 SCV000839903 pathogenic Breast-ovarian cancer, familial, susceptibility to, 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.
Institute of Human Genetics, University of Leipzig Medical Center RCV000031165 SCV001934564 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2020-10-05 criteria provided, single submitter clinical testing
Revvity Omics, Revvity Omics RCV000048532 SCV002023508 pathogenic not provided 2019-09-06 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000048532 SCV002047917 pathogenic not provided 2021-10-11 criteria provided, single submitter clinical testing The BRCA1 c.4357+1G>A variant (rs80358027), also known as IVS13+1G>A, is reported in the literature in multiple individuals affected with breast and/or ovarian cancer (Alemar 2016, Carter 2018, Pal 2004, Thomassen 2012). This variant is found on a single chromosome in the Genome Aggregation Database (1/251154 alleles), indicating it is not a common polymorphism. This variant abolishes the canonical splice acceptor site of intron 13, which is likely to disrupt gene function. Consistent with this, RNA analyses from a patient carrying this variant demonstrate skipping of exon 13, leading to a frameshift (Thomassen 2012). Based on available information, this variant is considered to be pathogenic. References: Alemar B et al. Prevalence of Hispanic BRCA1 and BRCA2 mutations among hereditary breast and ovarian cancer patients from Brazil reveals differences among Latin American populations. Cancer Genet. 2016 Sep;209(9):417-422. PMID: 27425403. Carter NJ et al. Germline pathogenic variants identified in women with ovarian tumors. Gynecol Oncol. 2018 Dec;151(3):481-488. PMID: 30322717. Pal T et al. BRCA1 and BRCA2 mutations in a study of African American breast cancer patients. Cancer Epidemiol Biomarkers Prev. 2004 Nov;13(11 Pt 1):1794-9. PMID: 15533909. Thomassen M et al. Characterization of BRCA1 and BRCA2 splicing variants: a collaborative report by ENIGMA consortium members. Breast Cancer Res Treat. 2012 Apr;132(3):1009-23. PMID: 21769658.
Sema4, Sema4 RCV000131879 SCV002537742 pathogenic Hereditary cancer-predisposing syndrome 2021-04-19 criteria provided, single submitter curation
Illumina Laboratory Services, Illumina RCV000031165 SCV004101329 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2023-07-11 criteria provided, single submitter clinical testing The BRCA1 c.4357+1G>A variant results in a substitution at the consensus splice donor site. A functional study conducted in patient cells demonstrated that this variant results in abnormal splicing which is predicted to result in a frameshift and premature termination of translation, leading to nonsense mediated mRNA decay (PMID: 21769658). Across a selection of the available literature, this variant has been identified in more than ten individuals with breast or ovarian cancer, including 5% of African American patients in a multi-center cohort (PMID: 21769658; PMID: 27425403; PMID: 29446198; PMID: 30322717; PMID: 31825140). This variant has also been detected in an individual with prostate cancer (PMID: 29368341). This variant is reported in the Genome Aggregation Database in one allele at a frequency of 0.000046 in the European (Finnish) population This variant has been classified as pathogenic by at least three submitters in ClinVar. Based on the available evidence, the c.4357+1G>A variant has been classified as pathogenic for hereditary breast and ovarian cancer.
Baylor Genetics RCV000031165 SCV004212699 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2023-10-21 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031165 SCV000053765 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2012-10-18 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031165 SCV000145068 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto RCV000167804 SCV000587392 pathogenic Hereditary breast ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000048532 SCV000591509 pathogenic not provided no assertion criteria provided clinical testing

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