ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.68-2A>G

dbSNP: rs769152395
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000167275 SCV000218118 uncertain significance Hereditary cancer-predisposing syndrome 2021-10-25 criteria provided, single submitter clinical testing 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). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. It cannot yet be ruled out that this variant may be hypomorphic and present with reduced risks and/or biallelic phenotype.
Invitae RCV000702378 SCV000831230 uncertain significance Hereditary breast ovarian cancer syndrome 2023-01-24 criteria provided, single submitter clinical testing 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.
Mendelics RCV000702378 SCV000838719 likely pathogenic Hereditary breast ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000988980 SCV001138940 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2019-05-28 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000167275 SCV001343729 uncertain significance Hereditary cancer-predisposing syndrome 2022-09-02 criteria provided, single submitter clinical testing 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000702378 SCV001363254 likely pathogenic Hereditary breast ovarian cancer syndrome 2019-08-12 criteria provided, single submitter clinical testing 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.

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