ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4163_4164delinsA (p.Thr1388fs) (rs276174843)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000509609 SCV000607797 pathogenic Hereditary cancer-predisposing syndrome 2017-01-06 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)
Breast Cancer Information Core (BIC) (BRCA2) RCV000031466 SCV000146385 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000509609 SCV000688854 pathogenic Hereditary cancer-predisposing syndrome 2017-07-17 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031466 SCV000326982 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031466 SCV000282388 pathogenic Breast-ovarian cancer, familial 2 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000044363 SCV000210745 pathogenic not provided 2018-07-10 criteria provided, single submitter clinical testing This combined deletion and insertion is denoted BRCA2 c.4163_4164delCTinsA at the cDNA level and p.Thr1388AsnfsX22 (T1388NfsX22) at the protein level. The surrounding sequence is TTAA[delCT][insA]TTTTTG. The variant causes a frameshift, which changes a Threonine to an Asparagine at codon 1388, and creates a premature stop codon at position 22 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 4163_4164delCTinsA, previously reported as BRCA2 4391delCTinsA using alternate nomenclature, has been observed in several individuals with Hereditary Breast and Ovarian Cancer syndrome (Kauff 2003, Alsop 2012, George 2013). We consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000203655 SCV000694747 pathogenic Hereditary breast and ovarian cancer syndrome 2016-05-02 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.4163_4164delinsA variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein due to nonsense mediated decay, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Leu2805fs). Mutation Taster predicts a damaging outcome for this variant. This variant was not found in 120446 control chromosomes, but has been reported in breast and ovarian cancer patients in the literature. In addition, multiple clinical laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant was classified as pathogenic.
Invitae RCV000203655 SCV000072376 pathogenic Hereditary breast and ovarian cancer syndrome 2018-08-16 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Thr1388Ilefs*22) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This particular truncation has been reported in individuals affected with breast and ovarian cancer, prostrate cancer and in an individual affected with breast hamartoma and lipoma (PMID: 29368341, 12698193, 23633455, 26681312, 10923033). This variant is also known as c.4163_4164delCTinsA, c.4163delCTinsA, and c.4391delCTinsA in the literature. ClinVar contains an entry for this variant (Variation ID: 37885). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000044363 SCV000600579 pathogenic not provided 2016-11-03 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000203655 SCV000587702 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000031466 SCV000054071 pathogenic Breast-ovarian cancer, familial 2 2009-12-23 no assertion criteria provided clinical testing

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