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

dbSNP: rs80358054

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000257895	SCV000076591	pathogenic	Hereditary breast ovarian cancer syndrome	2023-06-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 14 and/or activation of a cryptic splice site and introduces a premature termination codon (PMID: 26622941; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 55214). This variant is also known as IVS14-2A>G and 4604-2A>G. Disruption of this splice site has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 9333265, 11595708, 12960223, 24249303, 28179634). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 13 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.
Ambry Genetics	RCV000131885	SCV000186940	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-20	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 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, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Genologica Medica	RCV000077574	SCV000577932	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-01-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131885	SCV000909024	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-11-08	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the -2 position of intron 13 of the BRCA1 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, two different canonical splice site variants at this acceptor site, c.4485-1G>A and c.4485-1G>T, have been shown to cause out-of-frame splicing in RNA analysis of tumor- and carrier-derived RNA (PMID: 26622941, 31843900). This variant has been reported in at least four individuals affected with breast or ovarian cancer (PMID: 11595708, 28179634, 29673794, 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA1_004959) and additional suspected hereditary breast and ovarian cancer families (PMID: 9333265, 12960223, 24249303, 28111427, 29446198, 30203341). Other canonical splice site variants at this splice acceptor site have been reported as disease-causing in ClinVar (variation ID: 55213, 246501, 267551, 433715, 567954) and detected in individuals affected with breast or ovarian cancer (PMID: 9333265, 11595708, 12181777, 12960223, 24249303, 27553291, 28179634, 29446198, 31528241). This variant has not been identified 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 Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000257895	SCV001361788	pathogenic	Hereditary breast 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000235822	SCV003800236	pathogenic	not provided	2023-04-05	criteria provided, single submitter	clinical testing	The BRCA1 c.4485-2A>G variant (rs80358054), also known as IVS14-2A>G and 4604-2A>G for traditional nomenclature, is reported in multiple individuals with hereditary breast and ovarian cancer syndrome (Evans 2003, Park 2017, Rebbeck 2018, Shattuck-Eidens 1997). This variant is also reported in ClinVar (Variation ID: 55214). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant disrupts the canonical splice acceptor site of intron 14, which is likely to negatively impact gene function. Based on available information, this variant is considered to be pathogenic. References: Evans DG et al. Sensitivity of BRCA1/2 mutation testing in 466 breast/ovarian cancer families. J Med Genet. 2003 Sep;40(9):e107. PMID: 12960223. Park JS et al. Identification of a Novel BRCA1 Pathogenic Mutation in Korean Patients Following Reclassification of BRCA1 and BRCA2 Variants According to the ACMG Standards and Guidelines Using Relevant Ethnic Controls. Cancer Res Treat. 2017 Oct;49(4):1012-1021. PMID: 28111427. Rebbeck TR et al. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat. 2018 May;39(5):593-620. PMID: 29446198. Shattuck-Eidens D et al. BRCA1 sequence analysis in women at high risk for susceptibility mutations. Risk factor analysis and implications for genetic testing. JAMA. 1997 Oct 15;278(15):1242-50. PMID: 9333265.
PreventionGenetics, part of Exact Sciences	RCV003398637	SCV004111678	pathogenic	BRCA1-related condition	2023-03-13	criteria provided, single submitter	clinical testing	The BRCA1 c.4485-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant was reported in multiple individuals with breast and/or ovarian cancer (described as IVS14-2A>G, Shattuck-Eidens. 1997. PubMed ID: 9333265; Sekine. 2001. PubMed ID: 11595708; described as c.4604-2A>G, Evans. 2003. PubMed ID: 12960223). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is reported in ClinVar as pathogenic by the vast majority of labs (https://www.ncbi.nlm.nih.gov/clinvar/variation/55214/). Variants that disrupt the consensus splice acceptor site in BRCA1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics	RCV000077574	SCV004212768	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-09-08	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077574	SCV000109377	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2012-07-02	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077574	SCV000145103	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing