ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.4691dup (p.Thr1566fs)

gnomAD frequency: 0.00001  dbSNP: rs786204209
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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) RCV000241371 SCV000300779 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Labcorp Genetics (formerly Invitae), Labcorp RCV000168306 SCV000218989 pathogenic Hereditary breast ovarian cancer syndrome 2023-06-05 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 188309). This premature translational stop signal has been observed in individual(s) with pancreatic cancer and prostate cancer (PMID: 26546047, 27433846). This variant is present in population databases (rs786204209, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Thr1566Aspfs*9) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584).
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000241371 SCV000327069 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2015-10-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000509735 SCV000608247 pathogenic Hereditary cancer-predisposing syndrome 2021-07-13 criteria provided, single submitter clinical testing The c.4691dupC pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of C at nucleotide position 4691, causing a translational frameshift with a predicted alternate stop codon (p.T1566Dfs*9). This alteration was identified in an individuals with prostate and pancreatic cancer (Pritchard CC et al. N Engl J Med, 2016 Aug;375:443-53; Smith AL et al. Cancer Lett. 2016 Jan;370(2):302-12). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). 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 RCV001283923 SCV001469427 pathogenic not provided 2020-03-17 criteria provided, single submitter clinical testing The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.
GeneDx RCV001283923 SCV002546650 pathogenic not provided 2022-07-01 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with prostate cancer (Pritchard et al., 2016; Huang et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 4919dupC; This variant is associated with the following publications: (PMID: 27433846, 30720243, 29625052, 33084842)
Color Diagnostics, LLC DBA Color Health RCV000509735 SCV004362076 pathogenic Hereditary cancer-predisposing syndrome 2022-10-11 criteria provided, single submitter clinical testing This variant inserts 1 nucleotide in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with pancreatic cancer (PMID: 26546047, 31469826) and prostate cancer (PMID: 27433846). This variant has been identified in 1/251062 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000168306 SCV004847676 pathogenic Hereditary breast ovarian cancer syndrome 2019-03-22 criteria provided, single submitter clinical testing The p.Thr1566AspfsX9 variant in BRCA2 has been reported in 2 individuals with BRCA2-associated cancers (1 individual with prostate cancer and 1 individual with pancreatic cancer; Pritchard 2016, Smith 2016). It has also been identified in 1/113,456 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as Pathogenic on September 8, 2016 by the ClinGen-approved NAME expert panel (Variation ID 188309). It is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1566 and leads to a premature termination codon 9 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast and ovarian cancer syndrome. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000241371 SCV000591922 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735556 SCV000863694 pathogenic Breast and/or ovarian cancer 2014-07-11 no assertion criteria provided clinical testing

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