Submissions for variant NM_032043.3(BRIP1):c.627+5G>A

gnomAD frequency: 0.00001  dbSNP: rs745727200

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000218647	SCV000275563	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-09	criteria provided, single submitter	clinical testing	The c.627+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 5 in the BRIP1 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000234365	SCV000291054	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2023-09-12	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. This variant is present in population databases (rs745727200, gnomAD 0.0009%). This sequence change falls in intron 6 of the BRIP1 gene. It does not directly change the encoded amino acid sequence of the BRIP1 protein. It affects a nucleotide within the consensus splice site. 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 231653).
Color Diagnostics, LLC DBA Color Health	RCV000218647	SCV001350545	uncertain significance	Hereditary cancer-predisposing syndrome	2019-02-12	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267958	SCV002551205	likely pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV004567567	SCV005059290	uncertain significance	Familial cancer of breast	2024-01-04	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV003150982	SCV003839291	uncertain significance	not specified	2022-11-22	no assertion criteria provided	clinical testing	DNA sequence analysis of the BRIP1 gene demonstrated a sequence change in intron 6, c.627+5G>A. This change does not appear to have been previously described in individuals with BRIP1-related disorders. This sequence change has been described in the gnomAD database with a global frequency of 0.0008% (dbSNP rs745727200). Based on in-silico splice prediction programs, this sequence change is predicted to affect normal splicing of the BRIP1 gene, which could result in an abnormal protein, however functional studies have not been performed to prove this conclusively. The functional significance of this sequence change is not known at present and its contribution to this individual's disease phenotype cannot definitively be determined.