ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4411_4414AGAA[1] (p.Lys1472fs) (rs397507333)

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Total submissions: 10
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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) RCV000031483 SCV000300744 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 RCV000044410 SCV000072423 pathogenic Hereditary breast and ovarian cancer syndrome 2018-10-07 criteria provided, single submitter clinical testing This sequence change deletes 4 nucleotides from exon 11 of the BRCA2 mRNA (c.4415_4418delAGAA), causing a frameshift at codon 1472. This creates a premature translational stop signal (p.Lys1472Thrfs*6) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic. This particular variant has been reported in the literature in individuals affected with breast cancer and/or ovarian cancer (PMID: 24010542, 26681682, 15918047, 15131399). This variant has also been reported in an individual with colorectal cancer (PMID: 28195393). This variant is also known as 4643del4 or 4643delAGAA in the literature. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000213169 SCV000279255 pathogenic not provided 2018-07-02 criteria provided, single submitter clinical testing This deletion of four nucleotides in BRCA2 is denoted c.4415_4418delAGAA at the cDNA level and p.Lys1472ThrfsX6 (K1472TfsX6) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AGAA[delAGAA]CAAA. The deletion causes a frameshift, which changes a Lysine to a Threonine at codon 1472, 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.4415_4418delAGAA, previously reported as BRCA2 4643del4 and 4643delAGAA using alternate nomenclature, has been observed in individuals with familial or early-onset breast cancer (Pietschmann 2005, Konstantopoulou 2014, Eccles 2016). We consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000213169 SCV000296683 pathogenic not provided 2015-04-20 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031483 SCV000327030 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031483 SCV000489707 pathogenic Breast-ovarian cancer, familial 2 2016-11-14 criteria provided, single submitter clinical testing
Color RCV000771386 SCV000903714 pathogenic Hereditary cancer-predisposing syndrome 2018-02-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000044410 SCV000918980 pathogenic Hereditary breast and ovarian cancer syndrome 2018-04-02 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.4415_4418delAGAA (p.Lys1472ThrfsX6) 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 4.1e-06 in 243794 control chromosomes (gnomAD and publications). c.4415_4418delAGAA has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Lubinski 2004, Pietschmann 2005, Konstantopoulou 2014, Eccles 2016). 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 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031483 SCV000054088 pathogenic Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000044410 SCV000587712 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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