ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3751dup (p.Thr1251fs) (rs397507683)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000569057 SCV000673102 pathogenic Hereditary cancer-predisposing syndrome 2016-10-12 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 RCV000241325 SCV000326910 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Department of Medical Genetics,Oslo University Hospital RCV000241325 SCV000605631 pathogenic Breast-ovarian cancer, familial 2 2015-07-01 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000241325 SCV000300661 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000497278 SCV000210738 pathogenic not provided 2017-06-19 criteria provided, single submitter clinical testing This duplication of one nucleotide is denoted BRCA2 c.3751dupA at the cDNA level and p.Thr1251AsnfsX14 (T1251NfsX14) at the protein level. The normal sequence, with the base that is duplicated in brackets, is GGAA[dupA]CTTC. The duplication causes a frameshift, which changes a Threonine to an Asparagine at codon 1251, and creates a premature stop codon at position 14 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 3751dupA, previously reported as BRCA2 3976insA or 3979insA using alternative nomenclature, has been reported in individuals with breast and/or ovarian cancer (Yassaee 2002, Yazici 2002). We consider this variant to be pathogenic.
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000241325 SCV000746288 pathogenic Breast-ovarian cancer, familial 2 2017-12-03 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779989 SCV000916971 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-06 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.3751dupA (p.Thr1251AsnfsX14) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.2e-06 in 240830 control chromosomes (gnomAD). The variant, c.3751dupA, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Heramb_2018, Yassaee_2002, Yazici_2002). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.

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