Submissions for variant NM_032043.3(BRIP1):c.1936-1G>A

dbSNP: rs1555601204

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000566261	SCV000664829	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-11-26	criteria provided, single submitter	clinical testing	The c.1936-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 13 of the BRIP1 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. While the exact functional effect of the missing amino acids is unknown, the impacted region is critical for protein function (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV001289543	SCV001477494	likely pathogenic	Familial cancer of breast	2020-11-06	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001821665	SCV002069676	pathogenic	not provided	2021-02-16	criteria provided, single submitter	clinical testing	DNA sequence analysis of the BRIP1 gene demonstrated a sequence change in the canonical splice acceptor site of intron 13, c.1936-1G>A. This sequence change is absent from known population databases (gnomAD). This pathogenic sequence change is predicted to affect normal splicing of the BRIP1 gene and result in an abnormal protein. While this particular sequence change has not been reported in individuals with BRIP1-related caners, other loss of function variants in BRIP1 have been described in multiple individuals with ovarian or breast cancer (PMIDS: 17033622, 21964575).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001858150	SCV002282425	likely pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2021-06-02	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 13 of the BRIP1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRIP1 are known to be pathogenic (PMID: 16116423, 17033622, 21964575). This variant is not present in population databases (ExAC no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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: 480901).