Submissions for variant NM_007294.4(BRCA1):c.4986+5G>A

dbSNP: rs397509211

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000197490	SCV000253714	pathogenic	Hereditary breast ovarian cancer syndrome	2019-01-30	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing and/or protein function (PMID: 23239986, 23451180, 30209399). This variant has been observed in an individual affected with breast cancer (PMID: 23239986). ClinVar contains an entry for this variant (Variation ID: 96936). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 15 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein, but it affects a nucleotide within the consensus splice site of the intron.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000083057	SCV000326083	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	RCV000197490	SCV000918764	likely pathogenic	Hereditary breast ovarian cancer syndrome	2017-12-21	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.4986+5G>A variant (alternatively known as IVS16+5G>A and 5105+5G>A) involves the alteration of a conserved intronic nucleotide and is predicted to impact splicing by 4/5 splice prediction tools. Mutation taster also predicts a damaging outcome for this variant. This variant is absent in 244498 control chromosomes (gnomAD). This variant has been reported in breast and pancreatic cancer patients in the literature (Wappenschmidt_2012, Mandelker_2017) and functional studies show that it leads to the retention of 65 nucleotides of the 5' end of intron 15 which leads to premature truncation of the BRCA1 protein (p.Met1663Valfs*14) (Wappenschmidt_2012, Colombo_2013). Other similar variants (c.4986+3G>C, c.4986+4A>G, c.4986+5G>T and c.4986+6T>C) were found to cause the incorporation of the 65 intronic nucleotides [Wappenschmidt_2012, Vreeswijk_2009 (PMID: 18693280)]. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as likely pathogenic.
Ambry Genetics	RCV002345404	SCV002645636	pathogenic	Hereditary cancer-predisposing syndrome	2022-10-03	criteria provided, single submitter	clinical testing	The c.4986+5G>A intronic pathogenic mutation results from a G to A substitution 5 nucleotides after coding exon 14 in the BRCA1 gene. This alteration was identified in a cohort of Chinese ovarian cancer patients (Deng H et al. Mol Genet Genomic Med. 2019 Jun;7:e672). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. This alteration has been shown to lead to retention of 65 nucleotides of the affected intron leading to a predicted frameshift (Ambry internal data; Colombo M et al. PLoS ONE, 2013 Feb;8:e57173; Wappenschmidt B et al. PLoS ONE, 2012 Dec;7:e50800). This alteration was also shown to be non-functional in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Similar alterations have also been shown to lead to the same splice defect (Azzollini J et al. Eur. J. Intern. Med., 2016 Jul;32:65-71; Vreeswijk MP et al. Hum. Mutat., 2009 Jan;30:107-14). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Sharing Clinical Reports Project (SCRP)	RCV000083057	SCV000115131	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2011-01-24	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000083057	SCV000145236	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2013-03-25	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000083057	SCV001243877	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001578277	SCV001797973	likely pathogenic	Breast carcinoma	2021-08-24	no assertion criteria provided	clinical testing	Invasive Breast Carcinoma EST= + PRO = - HER2 = - KI = 70%
Center for Precision Medicine, Meizhou People's Hospital	RCV002250559	SCV002520802	likely pathogenic	Familial cancer of breast		no assertion criteria provided	literature only