ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3744_3747del (p.Ser1248fs) (rs80359403)

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Total submissions: 12
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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) RCV000031437 SCV000282382 pathogenic Breast-ovarian cancer, familial 2 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000044254 SCV000072267 pathogenic Hereditary breast and ovarian cancer syndrome 2018-11-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser1248Argfs*10) 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 the literature in individuals and families affected with breast/ovarian cancer (PMID: 26187060, 19656164, 16455195, 11802209, 18489799). This variant is also known as 3972del4 in the literature. ClinVar contains an entry for this variant (Variation ID: 37856). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000131096 SCV000186026 pathogenic Hereditary cancer-predisposing syndrome 2017-11-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000485903 SCV000296741 pathogenic not provided 2015-02-06 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031437 SCV000326909 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000485903 SCV000568466 pathogenic not provided 2018-05-21 criteria provided, single submitter clinical testing This deletion of four nucleotides in BRCA2 is denoted c.3744_3747delTGAG at the cDNA level and p.Ser1248ArgfsX10 (S1248RfsX10) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TTAG[delTGAG]GAAA. The deletion causes a frameshift which changes a Serine to an Arginine at codon 1248, and creates a premature stop codon at position 10 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 c.3744_3747delTGAG, also reported as BRCA2 3972_3975delTGAG or 3972del4 using alternate nomenclature, has been observed in several individuals with personal and family history with Hereditary Breast and Ovarian Cancer syndrome and is a recurrent variant in the Korean population (Kang 2002, Meindl 2002, Kim 2012, Minucci 2015, Kwong 2016, Song 2017). We consider this variant to be pathogenic.
Color RCV000131096 SCV000683579 pathogenic Hereditary cancer-predisposing syndrome 2015-06-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000044254 SCV000694716 pathogenic Hereditary breast and ovarian cancer syndrome 2017-02-06 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.3744_3747delTGAG (p.Ser1248Argfs) 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 (c.3785C>A, p.Ser1262X; c.3847_3848delGT, p.Val1283fs). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 118360 control chromosomes. The variant has been reported in numerous affected individuals in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Mendelics RCV000044254 SCV000838788 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031437 SCV000054042 pathogenic Breast-ovarian cancer, familial 2 2010-02-26 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031437 SCV000146289 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000044254 SCV000587680 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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