Submissions for variant NM_007294.4(BRCA1):c.4987-2A>G

dbSNP: rs397509212

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000258325	SCV001161631	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 = 0.998471
GeneDx	RCV000212189	SCV000210191	pathogenic	not provided	2014-07-29	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted BRCA1 c.4987-2A>G or IVS15-2A>G and consists of an A>G nucleotide substitution at the -2 position of intron 15 of the BRCA1 gene. The 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. BRCA1 c.4987-2A>G, previously reported as c.5106-2A>G, has been has been reported in association with hereditary breast and ovarian cancer (Meyer 2003, Thomassen 2012). The variant was predicted by Thomassen et al. (2012) to be pathogenic based on frequency information, multifactorial analysis and splicing results indicative of exon skipping and protein truncation. Based on the current evidence, we consider BRCA1 c.4987-2A>G to be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000258325	SCV000326096	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853015	SCV002231213	pathogenic	Hereditary breast ovarian cancer syndrome	2021-10-18	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 55345). This variant is also known as IVS16-2A>G. Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (PMID: 12938098, 21769658, 29446198). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 15 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). 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: 21769658, 31131967). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that disruption of this splice site does not substantially affect BRCA1 function (PMID: 30209399).
Ambry Genetics	RCV002336187	SCV002640407	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-06-29	criteria provided, single submitter	clinical testing	The c.4987-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 15 in the BRCA1 gene. This nucleotide position is highly conserved in available vertebrate species. One functional study found that this nucleotide substitution is functional in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). However, this alteration was predicted to be pathogenic using a multifactorial likelihood analysis (Parsons MT et al. Hum. Mutat. 2019 09;40(9):1557-1578). Additionally, this alteration has been shown to cause aberrant splicing of exon 15 skipping, which is a NMD-prone transcript (Thomassen M et al. Breast Cancer Res. Treat. 2012 Apr;132(3):1009-23). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000212189	SCV000591558	uncertain significance	not provided		no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000258325	SCV001238409	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro