Submissions for variant NM_007294.4(BRCA1):c.5152+7A>G

dbSNP: rs80358046

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000422346	SCV000530724	likely benign	not specified	2016-08-17	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000559883	SCV000636013	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-08-30	criteria provided, single submitter	clinical testing	This sequence change falls in intron 17 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 96940). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects BRCA1 function (PMID: 30209399). Studies have shown that this variant results in skipping of exon 17, but is expected to preserve the integrity of the reading-frame (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000776170	SCV000911267	likely benign	Hereditary cancer-predisposing syndrome	2017-12-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000422346	SCV001361789	uncertain significance	not specified	2019-08-09	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5152+7A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251212 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.5152+7A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800393	SCV002047172	uncertain significance	not provided	2021-05-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000776170	SCV002641070	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-19	criteria provided, single submitter	clinical testing	The c.5152+7A>G intronic alteration results from an A to G substitution 7 nucleotides after coding exon 16 in the BRCA1 gene. One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay. (Findlay GM et al. Nature, 2018 10;562:217-222). However, other functional studies have found this variant to be neutral (unpublished data, external communication). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). However, additional studies have suggested that this splicing impact may be incomplete, therefore the clinical impact of this abnormal splicing is unknown at this time (external communication). In addition, family history data suggests that this variant does not segregate well with disease, and one laboratory reports that this alteration has been confirmed to occur in trans with another pathogenic mutation in BRCA1 in an individual with no reported features of Fanconi anemia (external communication). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Sharing Clinical Reports Project (SCRP)	RCV000083061	SCV000115135	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2011-05-10	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000083061	SCV000145348	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000083061	SCV001243641	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro