rs769152395
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1_ModeratePM2PP3_StrongPP5
The NM_000059.4(BRCA2):c.68-2A>G variant causes a splice acceptor change. The variant allele was found at a frequency of 0.00000137 in 1,458,660 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_000059.4 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.68-2A>G | splice_acceptor_variant | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.68-2A>G | splice_acceptor_variant | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000404 AC: 1AN: 247642Hom.: 0 AF XY: 0.00000744 AC XY: 1AN XY: 134330
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1458660Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 725568
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | May 04, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 12, 2019 | Variant summary: BRCA2 c.68-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: 4/5 tools predict that the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 247642 control chromosomes (gnomAD). To our knowledge, c.68-2A>G has not been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (after 2014). All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2023 | Disruption of this splice site has been observed in individual(s) undergoing genetic testing. An analysis comparing the clinical and personal history of variant carriers with that of carriers of known benign or pathogenic variants showed inconclusive results for this variant (PMID: 33469799). 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. Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 3 (PMID: 33469799; Invitae). ClinVar contains an entry for this variant (Variation ID: 187538). This variant is present in population databases (rs769152395, gnomAD 0.0009%). This sequence change affects an acceptor splice site in intron 2 of the BRCA2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 2 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 02, 2022 | This variant causes an A to G nucleotide substitution at the -2 position of intron 2 of the BRCA2 gene. Splice site prediction tools indicate that this variant may have a significant impact on RNA splicing. RNA studies have confirmed that the variant disrupts splicing of the full-length transcript, however, the predominant product is a 6-basepair deletion in exon 3, resulting in the in-frame deletion of two amino acids p.Asp23_Leu24del, and an increase in the skipping of exon 3 (PMID: 33469799, 35979650; ClinVar accession ID: SCV000218118.6, SCV000831230.5). Functional studies have reported that this variant does not impact BRCA2 function in the complementation of Brca2-deficient mouse embryonic stem cells and in a homology-directed repair assay (PMID: 35979650). A carrier health history analysis for this variant compared against known benign and pathogenic variant carriers has reported that the pathogenicity of this variant was inconclusive but trending towards benign (PMID: 33469799). While a multifactorial analysis has reported likelihood ratios for pathogenicity based on tumor pathology, segregation and family history of 0.57, 0.28 and 0.79, respectively (PMID: 35979650). This variant has been identified in 1/247642 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 23, 2024 | The c.68-2A>G intronic variant results from an A to G substitution two nucleotides before coding exon 2 of the BRCA2 gene. 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 substantial expression of multiple abnormal transcripts including a splice variant which is predicted to result in an in-frame loss of two amino acids as well as one that results in skipping of coding exon 2 (also known as exon 3 in the literature) (Ambry internal data; Nix P et al. Fam Cancer, 2021 Jan; personal communication). The loss of coding exon 2 of is strongly associated with hereditary breast and ovarian cancer phenotype based on multifactorial analysis (Caputo SM et al. Oncotarget, 2018 Apr;9:17334-17348); however the functional and clinical impact of the small in-frame loss is unknown. Downstream functional studies showed that this alteration was able to rescue the growth defect in BRCA2-null mouse embryonic stem cells and that these surviving cells maintained partial activity in a homology directed DNA repair assay (personal communication). This alteration is also identified in patients who collectively have a phenotype that is not consistent with a high risk BRCA2 pathogenic variant (Nix P et al. Fam Cancer, 2021 Jan). Based on the available evidence, the clinical significance of this variant remains unclear. It cannot yet be ruled out that this variant may be hypomorphic and present with reduced risks and/or biallelic phenotype. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at