Submissions for variant NM_032043.3(BRIP1):c.2575+2dup

dbSNP: rs1555574711

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000584221	SCV000689347	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-02-26	criteria provided, single submitter	clinical testing	This variant causes duplication at +2 position in intron 18 of the BRIP1 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, this variant is expected to result in an absent or disrupted protein product. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRIP1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Mendelics	RCV000989992	SCV001140754	uncertain significance	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001046785	SCV001210701	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2019-11-28	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. Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 491448). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 18 of the BRIP1 gene. It does not directly change the encoded amino acid sequence of the BRIP1 protein, but it affects a nucleotide within the consensus splice site of the intron.
Ambry Genetics	RCV000584221	SCV002739563	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-12-07	criteria provided, single submitter	clinical testing	The c.2575+2dupT intronic variant, results from a duplication of one nucleotide two nucleotide positions after coding exon 17 of the BRIP1 gene. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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. 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. As such, this alteration is classified as likely pathogenic.