ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.632-2A>C

dbSNP: rs397507842
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000462608 SCV000549621 pathogenic Hereditary breast ovarian cancer syndrome 2023-08-04 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 7 of the BRCA2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. 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: 18819001, 30883759). ClinVar contains an entry for this variant (Variation ID: 409495). Disruption of this splice site has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 18819001, 29446198). This variant is not present in population databases (gnomAD no frequency).
Ambry Genetics RCV000562710 SCV000666122 uncertain significance Hereditary cancer-predisposing syndrome 2024-08-29 criteria provided, single submitter clinical testing The c.632-2A>C intronic variant results from an A to C substitution two nucleotides upstream from coding exon 7 in 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 experiments have shown coding exon 7 splicing alterations to express an in-frame transcript, known as 6q39_8 in the literature (Ambry internal data). This transcript has been shown to be able to perform homology directed repair in protein functional studies at a near wild-type level (Mesman, RLS et al. Genet Med 2020 08;22(8):1355-1365). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV004999463 SCV005624493 likely pathogenic not provided 2024-05-28 criteria provided, single submitter clinical testing The BRCA2 c.632-2A>C variant disrupts a canonical splice-acceptor site and is predicted to interfere with normal BRCA2 mRNA splicing. This variant has not been reported in individuals with BRCA2-related conditions in the published literature. This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as likely pathogenic.

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