Submissions for variant NM_007294.4(BRCA1):c.5074+2T>C

dbSNP: rs80358089

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)	RCV000031212	SCV001161641	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2019-06-18	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 = 0.999563
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031212	SCV000326134	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Invitae	RCV000465250	SCV000549302	pathogenic	Hereditary breast ovarian cancer syndrome	2023-04-24	criteria provided, single submitter	clinical testing	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: 31131967). For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 30209399). ClinVar contains an entry for this variant (Variation ID: 37631). This variant is also known as IVS17+2T>C. Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (PMID: 25556971, 27914478, 28717669, 29339979, 29446198). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 16 of the BRCA1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584).
Department of Medical Genetics, Oslo University Hospital	RCV000031212	SCV000564328	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-07-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000563483	SCV000660953	pathogenic	Hereditary cancer-predisposing syndrome	2018-12-26	criteria provided, single submitter	clinical testing	The c.5074+2T>C intronic pathogenic mutation results from a T to C substitution two nucleotides after coding exon 15 in the BRCA1 gene. This alteration has been previously reported in multiple patients undergoing genetic testing based on personal and/or family history concerning for hereditary breast and ovarian cancer (HBOC) syndrome (Trujillano D et al. J Mol Diagn. 2015 Mar;17:162-70; Lourenco J et al. Genet Mol Biol. Sao Paulo. 2004;27(4):500-504). 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.
Color Diagnostics, LLC DBA Color Health	RCV000563483	SCV000683248	pathogenic	Hereditary cancer-predisposing syndrome	2020-05-07	criteria provided, single submitter	clinical testing	This variant causes a T to C nucleotide substitution at the +2 position of intron 16 of the BRCA1 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. A study using peripheral blood-derived RNA from a carrier has shown that this variant impacts normal RNA splicing (PMID: 30159786). A viability assay using human haploid cell line has shown that this variant disrupts normal BRCA1 function (PMID: 30209399). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 25556971, 27914478, 29339979, 30159786, Color internal data). In addition, a multifactorial likelihood model using health history and tumor pathology data have suggested this variant have a high probability of being pathogenic (PMID: 31131967). 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 Pathogenic.
Mendelics	RCV000465250	SCV000839219	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000031212	SCV001140493	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000031212	SCV002512515	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-06-07	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderate
Baylor Genetics	RCV000031212	SCV004215175	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-03-31	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031212	SCV000053812	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2009-03-06	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031212	SCV000145290	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	RCV000465250	SCV000587453	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353976	SCV000591567	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000031212	SCV001237537	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro