Submissions for variant NM_032043.3(BRIP1):c.1473+4_1473+8del

dbSNP: rs730881650

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160365	SCV000210872	uncertain significance	not provided	2018-03-12	criteria provided, single submitter	clinical testing	This variant is denoted BRIP1 c.1473+4_1473+8delAGATA or IVS10+4_IVS10+8delAGATA and consists of a deletion of five nucleotides at the +4 to +8 position in intron 10 of the BRIP1 gene. The normal sequence, with the bases that are deleted in brackets, is Ggta[delagata]ttttttc, where the capital letters are exonic and lowercase are intronic. In silico analyses, which include splice predictors and evolutionary conservation, are inconsistent in their assessment as to whether or not the variant is damaging.? This variant was not observed in large population cohorts (Lek 2016). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. Based on currently available evidence, it is unclear whether BRIP1 c.1473+4_1473+8delAGATA is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000706610	SCV000835673	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2022-06-22	criteria provided, single submitter	clinical testing	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: 182373). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 10 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.
Color Diagnostics, LLC DBA Color Health	RCV000773171	SCV000906724	uncertain significance	Hereditary cancer-predisposing syndrome	2019-05-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160365	SCV001134005	uncertain significance	not provided	2018-12-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000773171	SCV001172133	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-11-21	criteria provided, single submitter	clinical testing	The c.1473+4_1473+8delAGATA intronic variant, located in intron 9 of the BRIP1 gene, results from a deletion of 5 nucleotides within intron 9 of the BRIP1 gene. This nucleotide region is generally 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). Based on the majority of available evidence to date, this variant is likely to be pathogenic.