Submissions for variant NM_032043.3(BRIP1):c.380-5A>G

gnomAD frequency: 0.00019  dbSNP: rs587782131

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130674	SCV000185560	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-05	criteria provided, single submitter	clinical testing	The c.380-5A>G intronic variant results from an A to G substitution 5 nucleotides upstream from coding exon 4 in the BRIP1 gene. This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive and 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.
Invitae	RCV000547580	SCV000633692	likely benign	Familial cancer of breast; Fanconi anemia complementation group J	2023-11-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000547580	SCV000895118	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130674	SCV000903771	likely benign	Hereditary cancer-predisposing syndrome	2015-07-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985642	SCV001134030	uncertain significance	not provided	2019-03-07	criteria provided, single submitter	clinical testing
Mendelics	RCV000990037	SCV001140801	uncertain significance	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000985642	SCV001822906	uncertain significance	not provided	2020-01-08	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000990037	SCV003928152	uncertain significance	Familial cancer of breast	2023-04-14	criteria provided, single submitter	clinical testing	The BRIP1 c.380-5A>G intronic change results in an A to G substitution at the -5 position of intron 4 of the BRIP1 gene. Algorithms that predict the impact of sequence changes on splicing are inconclusive. This variant has a maximum subpopulation frequency of 0.038% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). To our knowledge, this variant has not been reported in individuals with hereditary breast and ovarian cancer syndrome or Fanconi anemia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004532564	SCV004115570	uncertain significance	BRIP1-related disorder	2023-01-23	criteria provided, single submitter	clinical testing	The BRIP1 c.380-5A>G variant is predicted to interfere with splicing. To our knowledge, this variant has not been reported in the literature. It is reported in 0.038% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-59926622-T-C), which is higher than expected for a primary casue of disease. This variant is classified as a VUS and likely benign by submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/141947/). Although we suspect that this variant may be benign, at this time, the clinical significance is uncertain due to the absence of conclusive functional and genetic evidence.