Submissions for variant NM_007294.4(BRCA1):c.5406+5G>A

dbSNP: rs80358073

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077621	SCV000326301	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000077621	SCV000744584	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002345350	SCV002651479	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-01-30	criteria provided, single submitter	clinical testing	The c.5406+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 20 in the BRCA1 gene. This alteration, referred to as IVS22+5G>A, was reported to segregate with disease in one Dutch hereditary breast cancer family and RT-PCR analysis demonstrated that it results in exon 22 skipping and premature protein truncation (Petrij-Bosch A et al. Nat. Genet., 1997 Nov;17:341-5). A similar alteration at this position, c.5406+5G>C, has also been demonstrated to result in exon 22 skipping (Houdayer C et al Hum. Mutat. 2012 Aug; 33(8):1228-38). The c.5406+5G>C alteration was reported in two unrelated individuals with triple negative breast cancer at ages 38 and 31 and in 1 of 473 Greek breast/ovarian cancer patients with a positive family history (Fostira F et al. Breast Cancer Res. Treat., 2012 Jul;134:353-62; Konstantopoulou I et al, Clin. Genet. 2014 Jan; 85(1):36-42). One functional study found that c.5406+5G>A is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000077621	SCV000109424	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2011-12-07	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077621	SCV000145492	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	1998-08-26	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000077621	SCV000733586	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000077621	SCV001238308	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001723638	SCV001956028	pathogenic	not provided		no assertion criteria provided	clinical testing