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

dbSNP: rs80358137

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112530	SCV001161634	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 = 0.991891
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000112530	SCV000326180	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000522401	SCV000617447	pathogenic	not provided	2017-10-17	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.5153-1G>A or IVS17-1G>A and consists of a G>A nucleotidesubstitution at the -1 position of intron 17 of the BRCA1 gene. Using alternate nomenclature, this variant haspreviously been published as BRCA1 5272-1G>A. This variant destroys a canonical splice acceptor site and has beenshown to cause abnormal splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNAdecay or to an abnormal protein product (Beristain 2007, Sanz 2010, Steffensen 2014). This variant has beenreported in several breast/ovarian cancer families, and is considered a founder variant in certain Spanish populations(Osorio 2000, de la Hoya 2002, Diez 2003, Infante 2006, Infante 2010, de Juan Jimenez 2013, Hasmad 2015). Basedon the current evidence, we consider this variant to be pathogenic
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000112530	SCV000744594	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000522401	SCV001133615	pathogenic	not provided	2018-11-16	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 symptomatic patient, and not found in general population data. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Ambry Genetics	RCV001023627	SCV001185536	pathogenic	Hereditary cancer-predisposing syndrome	2024-12-10	criteria provided, single submitter	clinical testing	The c.5153-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 17 of the BRCA1 gene. This alteration has been seen in many hereditary breast and ovarian cancer families and is a putative Spanish founder mutation (Infante M et al. Clin. Genet., 2010 Jan;77:60-9; de Juan Jiménez I et al. Fam. Cancer, 2013 Dec;12:767-77; Azzollini J et al. Eur. J. Intern. Med., 2016 Jul;32:65-71). RNA splicing assays have demonstrated aberrant splicing of a single nucleotide deletion resulting in a transcript subject to nonsense-mediated decay (Ambry internal data; Sanz DJ et al. Clin. Cancer Res., 2010 Mar;16:1957-67; Steffensen AY et al. Eur. J. Hum. Genet., 2014 Dec;22:1362-8). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496373	SCV001579924	pathogenic	Hereditary breast ovarian cancer syndrome	2024-12-23	criteria provided, single submitter	clinical testing	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 altered protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (PMID: 10755399, 19912264, 20215541, 22460208, 23479189, 27062684). It has also been observed to segregate with disease in related individuals. This variant is also known as c.5272-1G>A. ClinVar contains an entry for this variant (Variation ID: 55429). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 20215541, 24667779, 30209399; internal data). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000112530	SCV004215190	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-03-13	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005394283	SCV006058334	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Fanconi anemia, complementation group S	2023-05-24	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112530	SCV000145352	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1999-12-30	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496373	SCV000587472	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000112530	SCV000733596	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000112530	SCV001243691	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro