ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4131_4132insTGAGGA (p.Thr1378Ter) (rs80359429)

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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) RCV000113276 SCV000324219 pathogenic Breast-ovarian cancer, familial 2 2016-10-18 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics RCV000215361 SCV000276996 pathogenic Hereditary cancer-predisposing syndrome 2015-07-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000113276 SCV000296512 pathogenic Breast-ovarian cancer, familial 2 2016-05-14 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000113276 SCV000326976 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Invitae RCV000465953 SCV000549711 pathogenic Hereditary breast and ovarian cancer syndrome 2019-01-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Thr1378*) 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 individuals with a personal and/or family history of breast cancer (PMID: 11890985, 25896959, 27376475, 20927582, 23096105) and an individual with pancreatic ductal adenocarcinoma (PMID: 25940717). This variant is also known as Ins 4359 (TGAGGA), 4359ins6, or 1377insXG (InsTGAGGA) in the literature. ClinVar contains an entry for this variant (Variation ID: 126037). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000485082 SCV000564776 pathogenic not provided 2018-06-14 criteria provided, single submitter clinical testing This insertion of six nucleotides is denoted BRCA2 c.4131_4132insTGAGGA at the cDNA level and p.Thr1378Ter (T1378X) at the protein level. The normal sequence, with the bases that are inserted in brackets, is AAAC[insTGAGGA]ACTC. The insertion creates a nonsense variant, which changes a Threonine to a premature stop codon. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.4131_4132insTGAGGA, previously reported as BRCA2 4359ins6, has been observed in a male breast cancer patient, in identical twins with personal and family histories of breast cancer, as well as in an individual with pancreatic cancer (Delgado 2002, Ding 2011, Holter 2015). We consider this variant to be pathogenic.
Color RCV000215361 SCV000688851 pathogenic Hereditary cancer-predisposing syndrome 2017-01-05 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000465953 SCV000694745 pathogenic Hereditary breast and ovarian cancer syndrome 2016-12-23 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.4131_4132insTGAGGA (p.Asn1377_Thr1378insX) 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.4222C>T/p.Gln1408X). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 120786 control chromosomes. However, it has been reported in multiple affected individuals. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000113276 SCV000839934 pathogenic Breast-ovarian cancer, familial 2 2018-04-25 criteria provided, single submitter clinical testing This c.4131_4132insTGAGGA (p.Asn1377_Thr1378insTer) variant in the BRCA2 gene has been reported in multiple breast cancer and pancreatic cancer patients [PMID: 11890985, 25940717] while not observed in general population according to gnomad database. This variant has been reported by multiple clinical test center as disease-causing according to ClinVar database. This variant is predicted to cause loss of function of normal protein through mRNA decay or producing a truncated protein, which is a known disease mechanism for this gene. Based on current evidences, this c.4131_4132insTGAGGA (p.Asn1377_Thr1378insTer) variant in the BRCA2 gene is classified as pathogenic.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113276 SCV000146378 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing

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