Submissions for variant NM_007294.4(BRCA1):c.5153-1G>C

dbSNP: rs80358137

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031224	SCV000244388	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 = 1
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048827	SCV000076840	pathogenic	Hereditary breast ovarian cancer syndrome	2022-10-26	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 18 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. 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: 21990134, 27553291). ClinVar contains an entry for this variant (Variation ID: 37643). This variant is also known as 5272-1G>C and IVS18-1G>C. Disruption of this splice site has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 8644702, 11149413, 19912264, 25896959). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 17 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000031224	SCV000296294	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-02-17	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031224	SCV000326181	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048827	SCV000699211	pathogenic	Hereditary breast ovarian cancer syndrome	2016-08-29	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.5153-1G>C variant involves the alteration of a conserved intronic nucleotide located in a known splice site with 5/5 splice prediction tools predict the loss of a splice site, although these predictions have yet to be functionally assessed. The variant of interest has not been observed in controls (ExAC, 1000 Gs, or ESP) and has been reported in multiple affected individuals. In addition, multiple reputable databases/clinical laboratories cite the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267804	SCV002550951	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002336099	SCV002644831	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-25	criteria provided, single submitter	clinical testing	The c.5153-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 17 of the BRCA1 gene. This mutation has been previously reported in breast cancer cohorts (Díez O et al. Hum Mutat, 2003 Oct;22:301-12; Dorling et al. N Engl J Med. 2021 02;384:428-439). One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Other alterations impacting the same acceptor site (c.5153-1G>A and c.5153-2delA) have been reported in multiple families of various ethnicities affected with breast and/or ovarian cancer and are both predicted to have a deleterious impact on splicing (Kiechle et al. Hum Mutat. 2000 Dec;16(6):529-30; Sinilnikova OM et al. Fam Cancer. 2006;5(1):15-20; Infante M et al. Clin. Genet., 2010 Jan;77:60-9; Sanz DJ et al. Clin. Cancer Res., 2010 Mar;16:1957-67; Pern et al. PLoS One. 2012;7(10):e47993; Wappenschmidt et al. PLoS One. 2012;7(12):e50800; de Juan Jiménez I et al. Fam. Cancer, 2013 Dec;12:767-77; Steffensen AY et al. Eur. J. Hum. Genet., 2014 Dec;22:1362-8; Kang E et al. Breast Cancer REs Treat. 2015 May;151(1):157-68; Azzollini J et al. Eur. J. Intern. Med., 2016 Jul;32:65-71). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Of note, this alteration is also referred to as 5272-1G>C and IVS18-1G>C in published literature. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor 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.
Baylor Genetics	RCV000031224	SCV004211757	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-12-04	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000048827	SCV004848394	pathogenic	Hereditary breast ovarian cancer syndrome	2020-06-19	criteria provided, single submitter	clinical testing	The c.5153-1G>C variant in BRCA1 has been reported in at least 10 individuals with BRCA1-related cancer (first reported by Johannson 1996 PMID: 8644702). It was absent from large population studies. This variant was classified as pathogenic on 08/10/15 by the ClinGen-approved ENIGMA expert panel (Variation ID 37643). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the BRCA1 gene is an established disease mechanism in autosomal dominant HBOC. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000031224	SCV005045947	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-05-27	criteria provided, single submitter	clinical testing	PS3; PM2_Supporting; PVS1_Strong (RNA); PP1
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV002267804	SCV005199699	pathogenic	not provided	2022-10-14	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031224	SCV000053824	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2007-06-13	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031224	SCV000145353	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1999-12-30	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000031224	SCV001243692	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
BRCAlab, Lund University	RCV000031224	SCV002588827	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-08-26	no assertion criteria provided	clinical testing