ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4058_4062del (p.Glu1353fs) (rs397507322)

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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) RCV000031456 SCV000300703 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000198983 SCV000255249 pathogenic Hereditary breast and ovarian cancer syndrome 2019-12-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu1353Glyfs*6) 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 a single family affected with breast cancer (PMID: 21318380). This variant is also known as c.4057_4061del5 in the literature. ClinVar contains an entry for this variant (Variation ID: 37875). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000223041 SCV000278848 pathogenic not provided 2018-03-14 criteria provided, single submitter clinical testing This deletion of five nucleotides in BRCA2 is denoted c.4058_4062delAAACG at the cDNA level and p.Glu1353GlyfsX6 (E1353GfsX6) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA2 c.4286_4290delAAACG. The normal sequence, with the bases that are deleted in brackets, is GATG[delAAACG]GACT. The deletion causes a frameshift, which changes a Glutamic Acid to a Glycine at codon 1353, and creates a premature stop codon at position 6 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.4058_4062delAAACG has been observed in at least one individual with breast cancer and a family history of breast and/or ovarian cancer (Tung 2015). We consider this variant to be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031456 SCV000326965 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031456 SCV000489640 likely pathogenic Breast-ovarian cancer, familial 2 2016-11-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000198983 SCV000694738 pathogenic Hereditary breast and ovarian cancer syndrome 2017-06-29 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.4058_4062delAAACG (p.Glu1353Glyfs) 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.4092_4093delAT [p.Ile1364fs). One in silico tool predicts a damaging outcome for this variant. This variant is absent from the large control database ExAC (0/120580 control chromosomes). In the literature, the variant has been identified in at least 1 breast cancer patient (Tung_Cancer_2014). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Color Health, Inc RCV000772117 SCV000905180 pathogenic Hereditary cancer-predisposing syndrome 2017-12-13 criteria provided, single submitter clinical testing
Ambry Genetics RCV000772117 SCV001183422 pathogenic Hereditary cancer-predisposing syndrome 2018-11-29 criteria provided, single submitter clinical testing The c.4058_4062delAAACG pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 5 nucleotides at nucleotide positions 4058 to 4062, causing a translational frameshift with a predicted alternate stop codon (p.E1353Gfs*6). This mutation has been reported in an Asian individual with hereditary breast and/or ovarian cancer (Rebbeck TR et al. Hum. Mutat. 2018 May;39(5):593-620). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Sharing Clinical Reports Project (SCRP) RCV000031456 SCV000054061 pathogenic Breast-ovarian cancer, familial 2 2013-10-23 no assertion criteria provided clinical testing

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