ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2429dup (p.Asn810fs) (rs397508967)

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Total submissions: 4
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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) RCV000257821 SCV000323457 pathogenic Breast-ovarian cancer, familial 1 2016-10-18 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000257821 SCV000325355 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Invitae RCV000525232 SCV000635849 pathogenic Hereditary breast and ovarian cancer syndrome 2017-02-13 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 10 of the BRCA1 mRNA (c.2429dupA), causing a frameshift at codon 810. This creates a premature translational stop signal (p.Asn810Lysfs*13) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). ClinVar contains an entry for this variant (Variation ID: 266262). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000525232 SCV000918685 likely pathogenic Hereditary breast and ovarian cancer syndrome 2017-10-30 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.2429dupA (p.Asn810LysfsX13) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 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. c.2515delC/ p.His839fsX7, c.2766delA/ p.Val923fsX77, etc). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 245390 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases 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.

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