ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.8754+1G>C

dbSNP: rs397508006
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001182890 SCV001348489 likely pathogenic Hereditary cancer-predisposing syndrome 2019-09-10 criteria provided, single submitter clinical testing This variant causes a G>C nucleotide substitution at the +1 position of intron 21 of the BRCA2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. A different variant at the same position c.8982+1G>T has been reported in an individual with early-onset breast cancer and is observed with the activation of a cryptic splice site, leading to a 46-nucleotide insertion from the 5' end of intron 21 (PMID: 18597679). This cryptic splice site use introduces a premature termination codon (PMID: 17011978, 21638052). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic.
Invitae RCV001243882 SCV001417069 pathogenic Hereditary breast ovarian cancer syndrome 2022-10-18 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 922702). For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 18597679). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 21 of the BRCA2 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 BRCA2 are known to be pathogenic (PMID: 20104584).

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