ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9808delG (p.Ala3270Profs) (rs398122622)

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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 RCV000217558 SCV000277283 pathogenic Hereditary cancer-predisposing syndrome 2015-07-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077051 SCV000328171 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000077051 SCV000301415 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000197732 SCV000253674 likely pathogenic Hereditary breast and ovarian cancer syndrome 2015-05-07 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 27 of the BRCA2 mRNA (c.9808delG), causing a frameshift at codon 3270. This creates a premature translational stop signal in the last exon of the BRCA2 mRNA (p.Ala3270Profs*5). It is expected to result in a truncated BRCA2 protein. This variant has been reported in an affected patient in the Universal Mutation Database (PMID: 22144684), and is not present in population databases. ClinVar contains an entry for this variant (RCV000077051). While truncating variants in BRCA2 are known to be pathogenic (PMID: 20104584), the pathogenicity of those located in this last coding exon is not clinically conclusive due to the observation of neutral truncating variants (PMID: 8896551, 18097605, 20104584). Because this variant is located in the last coding exon of BRCA2, it is expected to escape nonsense mediated decay (NMD). However, other downstream, truncating variants functionally evaluated as being deleterious have been reported in this exon (PMID: 17026620, 18593900, 18607349). An experimental study has shown that a stretch of 36 conserved residues (amino acids 3270-3305) in BRCA2 is required to interact with RAD51 to mediate homologous recombination during the repair of double-strand DNA breaks (PMID: 17515903). This suggests that the c.9808delG (p.Ala3270Profs*5) variant, which lies at the beginning of this conserved region, may impact BRCA2 protein function. For these reasons, this variant has been classified as Likely Pathogenic. Of note, a truncating mutation seen upstream of this varianthas recently been shown to not segregate strongly with disease (PMID: 25639900) and hence raises the possibilityof decreased penetrance for mutations inthe final exon of the BRCA2 protein.
Sharing Clinical Reports Project (SCRP) RCV000077051 SCV000108848 pathogenic Breast-ovarian cancer, familial 2 2012-10-02 no assertion criteria provided clinical testing

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