ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9945del (p.Glu3316fs) (rs431825381)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000083011 SCV000301421 uncertain significance Breast-ovarian cancer, familial 2 2019-06-05 reviewed by expert panel curation Premature stop codon is located between the recognised high-risk truncating variant c.9924C>G (p.Tyr3308Ter) and the known low-risk truncating variant c.9976A>T (p.Lys3326Ter).
GeneDx RCV000160314 SCV000210805 uncertain significance not provided 2016-08-02 criteria provided, single submitter clinical testing This deletion of one nucleotide in BRCA2 is denoted c.9945delA at the cDNA level and p.Glu3316AsnfsX2 (E3316NfsX2) at the protein level. The normal sequence, with the base that is deleted in braces, is GAAAAA[A]GAAC. The deletion causes a frameshift, which changes a Glutamic Acid to an Asparagine at codon 3316, and creates a premature stop codon at position 2 of the new reading frame. Using alternate nomenclature, this variant would be defined as BRCA2 10173delA. This variant was observed in 1/674 healthy controls in a breast cancer case-control study; however, of note, the mean age of controls was 49.5 years and some controls had a first degree relative with breast cancer (Malone 2006). BRCA2 c.9945delA was observed with an allele frequency of 0.1% (5/4264), including two homozygotes, in African Americans in the NHLBI Exome Sequencing Project. Although this variant results in a frameshift and premature stop codon, nonsense mediated decay is not expected to occur, and it is located just upstream of a well-known polymorphism that also results in a premature stop of translation (K3326X), suggesting that this region of the BRCA2 gene and the region beyond codon 3326 is not crucial for proper function. Based on currently available information, it is unclear whether this deletion is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000165269 SCV000215986 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-19 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),Insufficient or conflicting evidence,Insufficient evidence
Invitae RCV000204290 SCV000259466 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-28 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the BRCA2 gene (p.Glu3316Asnfs*2). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 103 amino acids of the BRCA2 protein. This variant is present in population databases (rs778530487, ExAC 0.03%), including two homozygous individuals found in the NHLBI Exome Sequencing Project database. This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 96890). 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). Experimental studies have not been performed for this variant, and the functional significance of the disrupted amino acids is currently unknown. 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.
Mendelics RCV000204290 SCV000838913 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000165269 SCV000906828 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000083011 SCV000115085 uncertain significance Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing

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