ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5319dup (p.Asn1774fs)

dbSNP: rs80357823
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Total submissions: 16
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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) RCV000074358 SCV000300238 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Labcorp Genetics (formerly Invitae), Labcorp RCV000048927 SCV000076940 pathogenic Hereditary breast ovarian cancer syndrome 2024-01-17 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn1774Glnfs*56) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer and pancreatic cancer (PMID: 7894491, 11938448, 18779604, 25940717, 27062684). It has also been observed to segregate with disease in related individuals. This variant is also known as c.5319_5320insC or c.5438insC. ClinVar contains an entry for this variant (Variation ID: 55523). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000131363 SCV000186339 pathogenic Hereditary cancer-predisposing syndrome 2021-11-23 criteria provided, single submitter clinical testing The c.5319dupC pathogenic mutation, located in coding exon 19 of the BRCA1 gene, results from a duplication of C at nucleotide position 5319, causing a translational frameshift with a predicted alternate stop codon (p.N1774Qfs*56). This mutation has been reported in numerous breast and/or ovarian cancer families (Castilla LH et al. Nat. Genet. 1994 Dec;8:387-91; Nedelcu R et al. Eur. J. Hum. Genet. 2002 Feb;10:150-2; Judkins T et al. Cancer Res. 2005 Nov;65:10096-103; Brooks GA et al. Cancer Biol. Ther. 2006 Sep;5:1098-102; Kurian AW et al. J. Clin. Oncol. 2008 Oct;26:4752-8; Azzollini J et al. Eur. J. Intern. Med. 2016 Jul;32:65-71). This mutation was also reported in an individual with pancreatic cancer who met NCCN BRCA1 and BRCA2 testing criteria (Holter S et al. J. Clin. Oncol. 2015 Oct;33:3124-9). Of note, this alteration is also designated as 5438insC and 5319_5320insC in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000478417 SCV000296278 pathogenic not provided 2023-06-13 criteria provided, single submitter clinical testing The BRCA1 c.5319dup (p.Asn1774Glnfs*56) variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature in affected individuals with breast and/or ovarian cancer (PMIDs: 11938448 (2002), 16267036 (2005), 18779604 (2008), 27062684 (2016), 30103829 (2018), and 32438681 (2020)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000074358 SCV000326261 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000478417 SCV000564751 pathogenic not provided 2024-02-14 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 5438dupC; This variant is associated with the following publications: (PMID: 28888541, 31794323, 32438681, 7894491, 11938448, 20104584, 27062684, 18779604, 16267036, 16931905, 26295337, 30103829, 25940717, 30787465)
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000048927 SCV000591611 pathogenic Hereditary breast ovarian cancer syndrome 2014-07-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000048927 SCV001363932 pathogenic Hereditary breast ovarian cancer syndrome 2019-05-03 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5319dupC (p.Asn1774GlnfsX56) 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 251376 control chromosomes. c.5319dupC has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Castilla_1994, Judkins_2005, Holter_2015, Azzollini_2016, Cardoso_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. Five submitters including an expert panel (ENIGMA) have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000478417 SCV001715191 pathogenic not provided 2020-11-30 criteria provided, single submitter clinical testing PVS1, PM2, PP5
Color Diagnostics, LLC DBA Color Health RCV000131363 SCV001734764 pathogenic Hereditary cancer-predisposing syndrome 2023-08-14 criteria provided, single submitter clinical testing This variant inserts 1 nucleotide in exon 20 of the BRCA1 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 is also known as c.5319_5320insC and 5438insC in the literature. This variant has been reported in individuals and families affected with breast and ovarian cancer (PMID: 7894491, 16912212, 18779604, 27062684, 30103829) and pancreatic cancer (PMID: 25940717). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Baylor Genetics RCV000074358 SCV004215044 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2023-07-29 criteria provided, single submitter clinical testing
OMIM RCV000074358 SCV000039538 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 1994-12-01 no assertion criteria provided literature only
Sharing Clinical Reports Project (SCRP) RCV000074358 SCV000053839 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2012-11-28 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000074358 SCV000145451 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2004-02-20 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto RCV000048927 SCV000587492 pathogenic Hereditary breast ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735454 SCV000863591 pathogenic Breast and/or ovarian cancer 2009-09-04 no assertion criteria provided clinical testing

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