ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4485-2A>G (rs80358054)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000257895 SCV000076591 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-10 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 13 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 individuals affected with breast and ovarian cancer (PMID: 9333265, 11595708, 12960223, 28179634, 24249303). This variant is also known as IVS14-2A>G and 4604-2A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 55214). 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000131885 SCV000186940 pathogenic Hereditary cancer-predisposing syndrome 2020-06-12 criteria provided, single submitter clinical testing The c.4485-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 13 in the BRCA1 gene. Also designated as IVS14-2A>G and 4604-2A>G in published literature, this alteration has been reported in several families with breast and/or ovarian cancers (Shattuck-Eidens D et al. JAMA. 1997 Oct 15;278(15):1242-50; Sekine M et al. Clin Cancer Res. 2001 Oct;7(10):3144-50; Evans DG et al. J Med Genet. 2003 Sep;40(9):e107; Nakamura S et al. Breast Cancer<span style="color:rgb(54, 43, 54); font-family:arial"> 2015 Sep;22(5):462-8). This alteration has also been reported with a carrier frequency of 1 in 7051 unselected breast cancer patients and 0 in 11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). In vivo studies conducted in an EOC cell line homozygous for a different alteration at this splice acceptor site, c.4485-1G>T, identified the presence of a novel transcript induced by abnormal splicing, resulting in the absence of BRCA1 protein (Fleury H et al. Genes Cancer, 2015 Sep;6:378-398). 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx RCV000235822 SCV000293465 pathogenic not provided 2017-08-21 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4485-2A>G or IVS13-2A>G and consists of an A>G nucleotide substitution at the -2 position of intron 13 of the BRCA1 gene. Using alternate nomenclature, this variant has previously been published as BRCA1 c.4604-2A>G and BRCA1 IVS14-2A>G. This variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been reported in association with breast and ovarian cancer (Shattuck-Eidens 1997, Sekine 2001, Kwong 2015, Nakamura 2015). Based on the current evidence, we consider this variant to be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077574 SCV000325987 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Genologica Medica RCV000077574 SCV000577932 pathogenic Breast-ovarian cancer, familial 1 2017-01-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131885 SCV000909024 likely pathogenic Hereditary cancer-predisposing syndrome 2019-04-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000257895 SCV001361788 pathogenic Hereditary breast and ovarian cancer syndrome 2019-08-16 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4485-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: five predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251076 control chromosomes (gnomAD). c.4485-2A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Shattuck-Eidens_1997, Sekine_2001, Park_2017, Ahmadloo_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as pathogenic (3x) / likely pathogenic (3x). Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000077574 SCV000109377 uncertain significance Breast-ovarian cancer, familial 1 2012-07-02 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077574 SCV000145103 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing

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