ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1204del (p.Glu402fs)

dbSNP: rs80357859
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Total submissions: 15
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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) RCV000111566 SCV000299557 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000111566 SCV000324983 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2015-10-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000573323 SCV000661096 pathogenic Hereditary cancer-predisposing syndrome 2021-11-26 criteria provided, single submitter clinical testing The c.1204delG pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 1204, causing a translational frameshift with a predicted alternate stop codon (p.E402Sfs*8). This alteration has been reported in multiple families with hereditary breast and ovarian cancer (Machackova E et al. BMC Cancer, 2008 May;8:140; Struewing JP et al. Am. J. Hum. Genet., 1995 Jul;57:1-7). 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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Counsyl RCV000111566 SCV000785771 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2017-11-27 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000656644 SCV000858440 pathogenic not provided 2017-12-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000047378 SCV000918670 pathogenic Hereditary breast ovarian cancer syndrome 2021-04-02 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.1204delG (p.Glu402SerfsX8) 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 250852 control chromosomes. c.1204delG has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted 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.
Genetic Services Laboratory, University of Chicago RCV000656644 SCV002069050 pathogenic not provided 2017-12-11 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002483061 SCV002793492 pathogenic Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S 2021-12-01 criteria provided, single submitter clinical testing
GeneDx RCV000656644 SCV004168143 pathogenic not provided 2023-11-13 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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (PMID: 18489799, 7611277); 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 1323delG; This variant is associated with the following publications: (PMID: 7611277, 18489799, 27533253, 29446198, 26207792, 35912641)
Labcorp Genetics (formerly Invitae), Labcorp RCV000047378 SCV000075391 pathogenic Hereditary breast ovarian cancer syndrome 2014-11-06 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000111566 SCV000144030 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 1997-04-02 no assertion criteria provided clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000656644 SCV000778771 pathogenic not provided 2017-12-07 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000656644 SCV001553518 pathogenic not provided no assertion criteria provided clinical testing The BRCA1 p.Glu402Serfs*8 variant was identified in 7 of 2116 proband chromosomes (frequency: 0.0033) from individuals or families with hereditary breast and ovarian cancer (Enyedi 2016, Machackova 2008, Struewing 1995). The variant was also identified in dbSNP (ID: rs80357859) as “With Pathogenic allele”, ClinVar (as pathogenic by 9 submitters, reviewed by expert panel), LOVD 3.0 (3x as pathogenic). The variant was not identified in UMD-LSDB. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Glu402Serfs*8 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 402 and leads to a premature stop codon at position 409. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 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.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute RCV000656644 SCV002034323 pathogenic not provided no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000656644 SCV002035706 pathogenic not provided no assertion criteria provided clinical testing

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