Submissions for variant NM_007294.4(BRCA1):c.5333-1G>C

dbSNP: rs80358126

Total submissions: 6

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	RCV000112620	SCV000326276	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001182076	SCV001347406	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-11-10	criteria provided, single submitter	clinical testing	This variant causes a G to C nucleotide substitution at the -1 position of intron 20 of the BRCA1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, two different canonical splice site variants at this splice acceptor site have been reported to cause the out-of-frame skipping of exon 21 (PMID: 23239986, 29310832). A functional study has reported that this variant impacts BRCA1 function in a haploid human cell proliferation assay (PMID: 30209399). This variant has been reported in an individual affected with breast cancer (PMID: 19215791). Other canonical splice acceptor site variant in intron 20 have been reported as disease-causing in ClinVar (variation ID 55533, 55535, 55536, 267600, 449937) and reported in individuals and families affected with breast cancer (PMID: 19941162, 23239986, 29310832, 30350268). 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 Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001390969	SCV001592879	pathogenic	Hereditary breast ovarian cancer syndrome	2021-04-16	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 20 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). This variant has been observed in individual(s) with breast cancer (PMID: 19215791). This variant is also known as 5452-1G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 55534). 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, but this prediction has not been confirmed by published transcriptional studies. Experimental studies have shown that this variant affects BRCA1 protein function (PMID: 30209399).
Ambry Genetics	RCV001182076	SCV002640810	pathogenic	Hereditary cancer-predisposing syndrome	2020-07-08	criteria provided, single submitter	clinical testing	The c.5333-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 20 of the BRCA1 gene. This alteration was identified in a large, worldwide study of BRCA1/2 mutation-positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). Additionally, a functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature. 2018 10;562:217-222). 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112620	SCV000145463	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000112620	SCV001238190	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro