ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3865_3868del (p.Lys1289fs) (rs80359412)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000216772 SCV000274990 pathogenic Hereditary cancer-predisposing syndrome 2016-04-08 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),Other acmg-defined mutation (i.e. initiation codon or gross deletion)
Breast Cancer Information Core (BIC) (BRCA2) RCV000031443 SCV000146321 pathogenic Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000044292 SCV000586946 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-18 criteria provided, single submitter clinical testing
Color RCV000216772 SCV000683587 pathogenic Hereditary cancer-predisposing syndrome 2017-02-24 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031443 SCV000326930 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000031443 SCV000744447 pathogenic Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000031443 SCV000733251 pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000412719 SCV000225168 pathogenic not provided 2014-09-26 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031443 SCV000300678 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000412719 SCV000490434 pathogenic not provided 2018-07-26 criteria provided, single submitter clinical testing This deletion of four nucleotides in BRCA2 is denoted c.3865_3868delAAAT at the cDNA level and p.Lys1289AlafsX3 (K1289AfsX3) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TAAT[delAAAT]GCCA. The deletion causes a frameshift, which changes a Lysine to an Alanine at codon 1289, and creates a premature stop codon at position 3 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.3865_3868delAAAT, previously reported as 4093del4 or 4093delAAAT, has been reported in several individuals with a personal or family history of early-onset breast or ovarian cancer (Borg 2010, Becker 2012, Song 2014). We consider this variant to be pathogenic.
GeneKor MSA RCV000044292 SCV000693566 pathogenic Hereditary breast and ovarian cancer syndrome 2017-11-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000044292 SCV000694727 pathogenic Hereditary breast and ovarian cancer syndrome 2016-09-06 criteria provided, single submitter clinical testing Variant summary: The c.3865_3868delAAAT (p.Lys1289Alafs) variant in the BRCA2 gene is a frameshift change predicted to cause a loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay, which is a known disease mechanism in HBOC. The variant has been reported in multiple affected individuals and is absent from the large control population dataset of EXAC. The results of the functional study have shown that patient-derived lymphocytes carrying this variant exhibit increased chromosomal radiosensitivity in metaphase-based radiation assay, confirming deleterious outcome for this variant (Becker_2012). Lastly, multiple reputable databases/diagnostic centers classified the variant of interest as Pathogenic. Taken together, the variant was classified as Pathogenic.
Invitae RCV000044292 SCV000072305 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-22 criteria provided, single submitter clinical testing This sequence change deletes 4 nucleotides in exon 11 of the BRCA2 mRNA (c.3865_3868delAAAT), causing a frameshift at codon 1289. This creates a premature translational stop signal (p.Lys1289Alafs*3) and is expected to result in an absent or disrupted protein product. This variant has been reported in the literature in individuals with familial breast and ovarian cancer (PMID: 11102978, 22729890, 20104584). This variant is also known as 4093delAAAT or 4093del4 in the literature. ClinVar contains an entry for this variant (Variation ID: 37862). An experimental study has shown that patient-derived lymphocytes carrying this variant exhibit increased chromosomal radiosensitivity in metaphase-based radiation assay (PMID: 22729890). 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 RCV000031443 SCV000296635 pathogenic Breast-ovarian cancer, familial 2 2015-08-12 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031443 SCV000054048 pathogenic Breast-ovarian cancer, familial 2 2008-03-27 no assertion criteria provided clinical testing

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