rs786203700
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_ModeratePP3_StrongPP5
The NM_032043.3(BRIP1):c.206-2A>G variant causes a splice acceptor change. The variant allele was found at a frequency of 0.00000807 in 1,611,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_032043.3 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRIP1 | NM_032043.3 | c.206-2A>G | splice_acceptor_variant | ENST00000259008.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRIP1 | ENST00000259008.7 | c.206-2A>G | splice_acceptor_variant | 1 | NM_032043.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152172Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250636Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135608
GnomAD4 exome AF: 0.00000822 AC: 12AN: 1459600Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5AN XY: 726234
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152172Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74356
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 16, 2024 | Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant demonstrated to result in abnormal splicing; however, the effect on protein function is unknown (External communication with Ambry Genetics and Invitae); Observed in individuals with breast, ovarian, or other cancer, but also in unaffected controls (PMID: 26720728, 29368626, 32522261, 35988656); This variant is associated with the following publications: (PMID: 26720728, 31589614, 35988656, 32522261, 29368626) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2023 | BRIP1: PVS1:Strong, PM2 - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 18, 2023 | This variant causes an A to G nucleotide substitution at the canonical -2 position of intron 3 splice acceptor site of the BRIP1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. An RNA study at an external laboratory has shown that this variant results in abnormal splicing in clinical samples tested and is expected to result in an absent or non-functional protein product (ClinVar SCV000217950.5). A subsequent RNA study has shown that this variant results in transcripts with an in-frame deletion of 3 or 4 amino acids, and functional consequence of these alternate transcripts is not clear (ClinVar SCV000217950.5). This variant has been observed in individuals affected with breast and ovarian cancer (PMID: 26720728, 29368626; Color internal data) and in an unaffected individual (PMID: 32522261). This variant has been identified in 1/250636 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to the contradictory RNA study results, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 18, 2023 | The c.206-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 3 in the BRIP1 gene. In one study of 1915 women with ovarian cancer, who were unselected for age at diagnosis or family history, this variant was reported in a patient with serous ovarian cancer diagnosed at age 61 (Norquist BM et al. JAMA Oncol. 2016 Apr;2:482-90).This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in a transcript predicted to lead to proteins with an in-frame deletion of 3 amino acids and 4 amino acids; however, the exact functional impact of the deleted amino acids are unknown at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Ovarian neoplasm;C1836860:Fanconi anemia complementation group J Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 22, 2016 | - - |
Fanconi anemia complementation group J Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 09, 2019 | - - |
Ovarian neoplasm Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Department of Molecular Diagnostics, Institute of Oncology Ljubljana | Apr 02, 2020 | - - |
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 08, 2023 | This sequence change affects an acceptor splice site in intron 3 of the BRIP1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in two alternative in-frame transcripts. These alternative transcripts, one with a loss of 3 amino acid residues and the other with a loss of 4 amino acid residues, are expected to preserve the integrity of the reading-frame and as such, their functional consequence cannot be determined. This variant is present in population databases (rs786203700, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with ovarian cancer and breast cancer (PMID: 26720728, 32522261). ClinVar contains an entry for this variant (Variation ID: 187396). Studies have shown that disruption of this splice site results in the activation of two different cryptic splice sites in exon 4, but the impact on the resulting protein products is unknown (Invitae). 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. - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 12, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at