ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.1296_1297del (p.Asn433fs) (rs80359276)

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Total submissions: 17
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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) RCV000031317 SCV000300417 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 RCV000043775 SCV000071788 pathogenic Hereditary breast and ovarian cancer syndrome 2020-07-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn433Glnfs*18) 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 affected breast cancer (PMID: 25682074, 28008555), and an individual with a history of Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 37736). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000162900 SCV000213387 pathogenic Hereditary cancer-predisposing syndrome 2018-12-13 criteria provided, single submitter clinical testing The c.1296_1297delGA pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 1296 to 1297, causing a translational frameshift with a predicted alternate stop codon (p.N433Qfs*18). This mutation was identified in a female diagnosed with triple negative breast cancer (Wong-Brown MW et al. Breast Cancer Res. Treat. 2015 Feb;150:71-80), and in a male diagnosed with breast cancer (Pritzlaff M et al. Breast Cancer Res. Treat. 2017 Feb;161:575-586). This alteration was identified in a cohort German patients considered to be at increased risk for HBOC syndrome (Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295:1227-1238). In a large, clinic-based BRCA1/2 testing cohort in Norway, this variant was detected in one family (Heramb C et al. Hered Cancer Clin Pract. 2018 Jan;16:3). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000031317 SCV000296615 pathogenic Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
GeneDx RCV000255901 SCV000321451 pathogenic not provided 2018-06-01 criteria provided, single submitter clinical testing This deletion of two nucleotides in BRCA2 is denoted c.1296_1297delGA at the cDNA level and p.Asn433GlnfsX18 (N433QfsX18) at the protein level. The normal sequence, with the bases that are deleted in brackets, is CAGA[delGA]ACAA. This variant is also known as BRCA2 1524_1525delGA, using alternate nomenclature. The deletion causes a frameshift which changes an Asparagine to a Glutamine at codon 433, and creates a premature stop codon at position 18 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.1296_1297delGA has been observed in at least one individual with triple negative breast cancer, one individual with male breast cancer, and one individual who underwent multi-gene panel testing due to a personal history of a Lynch-syndrome associated cancer and/or colon polyps (Wong-Brown 2015, Yurgelun 2015, Pritzlaff 2016). We consider this variant to be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031317 SCV000326533 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031317 SCV000487833 likely pathogenic Breast-ovarian cancer, familial 2 2015-11-21 criteria provided, single submitter clinical testing
Department of Medical Genetics, Oslo University Hospital RCV000031317 SCV000605626 pathogenic Breast-ovarian cancer, familial 2 2015-07-01 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000031317 SCV000744406 pathogenic Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000043775 SCV000916994 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-11 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.1296_1297delGA (p.Asn433GlnfsX18) 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 was absent in 120444 control chromosomes (ExAC). The variant, c.1296_1297delGA, has been reported in the literature in individuals affected with either sporadic or Hereditary Breast and Ovarian Cancer (Wong-Brown 2015, Pritzlaff 2017, Meisel 2017, Lang 2017). 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. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation; 8 laboratories classified the variant as pathogenic, and 1 as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000255901 SCV001247637 pathogenic not provided 2019-02-01 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000031317 SCV001428739 pathogenic Breast-ovarian cancer, familial 2 2020-01-27 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000255901 SCV001446782 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031317 SCV000053922 pathogenic Breast-ovarian cancer, familial 2 2010-10-18 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031317 SCV000145847 pathogenic Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000031317 SCV000733226 pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357962 SCV001553576 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Asn433GlnfsX18 variant was identified in 2 of 5484 proband chromosomes (frequency: 0.00036) from individuals or families with male breast cancer (Pritzlaff_2016_28008555), triple negative breast cancer (Wong-Brown_2015_25682074), and Lynch syndrome (Yurgelun_2017_28135145). The variant was also identified in dbSNP (ID: rs80359276) as “With Pathogenic allele”, ClinVar (as pathogenic reviewed by expert panel), Clinvitae (5x as [pathogenic), LOVD 3.0 (7x), UMD-LSDB (2x as causal), BIC Database (3x as pathogenic), and ARUP Laboratories (as definitely pathogenic) databases. The variant was not identified in Cosmic, MutDB, or Zhejiang Colon Cancer Database. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Asn433GlnfsX18 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 433 and leads to a premature stop codon at position 450. 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.

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