ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3436G>T (p.Glu1146Ter) (rs1237049560)

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Total submissions: 5
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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) RCV000661493 SCV000783778 pathogenic Breast-ovarian cancer, familial 2 2017-12-15 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics RCV000509826 SCV000608236 pathogenic Hereditary cancer-predisposing syndrome 2018-11-23 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Color RCV000509826 SCV000912368 pathogenic Hereditary cancer-predisposing syndrome 2017-11-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780006 SCV000916996 likely pathogenic Hereditary breast and ovarian cancer syndrome 2017-12-15 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.3436G>T (p.Glu1146X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., p.Phe1182fsX1 and p.Lys1191fsX6). One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/245794 control chromosomes at a frequency of 0.0000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). One clinical diagnostic laboratory classified this variant as pathogenic. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic.
Invitae RCV000780006 SCV001234951 pathogenic Hereditary breast and ovarian cancer syndrome 2019-11-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu1146*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 441504). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.

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