ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.4405_4409del (p.Asp1469fs) (rs397507331)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 11
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031480 SCV000300740 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 RCV000160289 SCV000210750 pathogenic not provided 2017-08-04 criteria provided, single submitter clinical testing This deletion of five nucleotides in BRCA2 is denoted c.4405_4409delGACAT at the cDNA level and p.Asp1469LysfsX11 (D1469KfsX11) at the protein level. Using alternate nomenclature, this variant may be defined as BRCA2 4633_4637delGACAT, 4633del5, or 4404_4408delTGACA. The normal sequence, with the bases that are deleted in brackets, is TTCT[delGACAT]AAGA. The deletion causes a frameshift, which changes an Aspartic Acid to a Lysine at codon 1469 and creates a premature stop codon at position 11 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.4405_4409delGACAT has been observed in at least one individual with triple negative breast cancer (Wong-Brown 2015). We consider this variant to be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031480 SCV000327027 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031480 SCV000488393 likely pathogenic Breast-ovarian cancer, familial 2 2016-03-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV000566803 SCV000665983 pathogenic Hereditary cancer-predisposing syndrome 2019-02-23 criteria provided, single submitter clinical testing The c.4405_4409delGACAT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 5 nucleotides between positions 4405 and 4409, causing a translational frameshift with a predicted alternate stop codon (p.D1469Kfs*11). This alteration was reported in one individual from a cohort of 774 Australian and Polish women with triple negative breast cancer (Wong-Brown MW et al. Breast Cancer Res. Treat. 2015 Feb;150(1):71-80). 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.
Color Health, Inc RCV000566803 SCV000683617 pathogenic Hereditary cancer-predisposing syndrome 2015-04-07 criteria provided, single submitter clinical testing
Invitae RCV000257920 SCV001235140 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asp1469Lysfs*11) 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 observed in an individual affected with breast cancer (PMID: 25682074). ClinVar contains an entry for this variant (Variation ID: 37899). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000257920 SCV001467740 pathogenic Hereditary breast and ovarian cancer syndrome 2020-12-28 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.4405_4409delGACAT (p.Asp1469LysfsX11) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 247790 control chromosomes (gnomAD). c.4405_4409delGACAT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Wong-Brown_2015, Crawford_2017, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other ClinVar submitters (including two expert panels; evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031480 SCV000054085 pathogenic Breast-ovarian cancer, familial 2 2010-08-18 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000257920 SCV000587711 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000031480 SCV000591903 pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing The BRCA2 p.Asp1469LysfsX11 variant was not identified in the literature, nor was it identified in the NHLBI Exome Sequencing Project, Exome Aggregation Consortium (March 14, 2016), COSMIC, Clinvitae, BIC, BRCA Share UMD, ARUP Laboratories, LOVD Fanconi’s Anaemia and MutDB. The variant was identified DbSNP dbSNP (ID: rs397507331) as “With Pathogenic allele”. In the ClinVar database the variant was identified as pathogenic allele by the Sharing Clinical Reports Project, by GeneDx and Molecular Genetics Diagnostic Laboratory-Children Hospital of Eastern Ontario. The p.Asp1469LysfsX11deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1469 and leads to a premature stop codon 11 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.