ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7525dup (p.Ser2509fs) (rs80359656)

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Total submissions: 9
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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) RCV000076998 SCV000301172 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Counsyl RCV000076998 SCV000488461 likely pathogenic Breast-ovarian cancer, familial 2 2016-04-07 criteria provided, single submitter clinical testing
GeneDx RCV000486010 SCV000571248 pathogenic not provided 2016-08-02 criteria provided, single submitter clinical testing This duplication of one nucleotide in BRCA2 is denoted c.7525dupA at the cDNA level and p.Ser2509LysfsX30 (S2509KfsX30) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA2 7753dupA. The normal sequence, with the base that is duplicated in braces, is AGGC[A]GTCT. The duplication causes a frameshift which changes a Serine to a Lysine at codon 2509, and creates a premature stop codon at position 30 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000486010 SCV000600752 pathogenic not provided 2016-10-06 criteria provided, single submitter clinical testing
Color RCV000580386 SCV000683883 pathogenic Hereditary cancer-predisposing syndrome 2017-05-05 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588389 SCV000695075 likely pathogenic Hereditary breast and ovarian cancer syndrome 2017-05-26 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.7525dupA (p.Ser2509Lysfs) 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. c.7543dupA, p.Thr2515fs). One in silico tool predicts a damaging outcome for this variant. The variant of interest has not been found in a large, broad control population, ExAC in 120960 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.
Invitae RCV000588389 SCV000759218 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-10 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser2509Lysfs*30) 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 been reported in an individual in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 91481). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000076998 SCV000108795 pathogenic Breast-ovarian cancer, familial 2 2012-03-14 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000076998 SCV000147113 pathogenic Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing

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