ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8023A>G (p.Ile2675Val) (rs397507954)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132001 SCV000187060 likely pathogenic Hereditary cancer-predisposing syndrome 2018-02-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Functionally-validated splicing mutation,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000258421 SCV000327800 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000258421 SCV000785232 pathogenic Breast-ovarian cancer, familial 2 2017-06-20 criteria provided, single submitter clinical testing
GeneKor MSA RCV000045390 SCV000821715 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-08-01 criteria provided, single submitter clinical testing
Invitae RCV000045390 SCV000073403 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-31 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 2675 of the BRCA2 protein (p.Ile2675Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in many individuals and families affected with breast and/or ovarian cancer (PMID: 18424508, 23683081, 24249303, 25802882, 26757417, 27157322, 27741520). ClinVar contains an entry for this variant (Variation ID: 52475). Experimental RT-PCR and mini-gene splicing assays have shown that this sequence change creates a strong donor splice site, resulting in the removal of 309 nucleotides (r.8023_8331del) of exon 18 and the in-frame deletion of 103 amino acid residues (p.Ile2675_Lys2777del) (PMID: 18424508, 22505045, 27157322, 28339459) At least three different missense substitutions within the deleted region of BRCA2 (p.Thr2722Arg, p.Asp2723Gly, p.Asp2723His) are reported to be deleterious (PMID: 12145750, 21990134, 15290653, 16489001). This indicates that the residues included in the deleted region are important for BRCA2 protein function. For these reasons, this variant has been classified as Pathogenic.

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