ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5266C>T (p.Gln1756Ter) (rs397509247)

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Total submissions: 8
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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) RCV000257437 SCV000323854 pathogenic Breast-ovarian cancer, familial 1 2016-10-18 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 RCV000257437 SCV000326230 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000657590 SCV000779327 pathogenic not provided 2017-11-22 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5266C>T at the cDNA level and p.Gln1756Ter (Q1756X) at the protein level. Using alternate nomenclature, this variant would be described as BRCA1 5385C>T. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in at least two individuals with a personal history of breast cancer (Stoppa-Lyonnet 1997, Kang 2015) and is considered pathogenic.
Color Health, Inc RCV000774930 SCV000908987 pathogenic Hereditary cancer-predisposing syndrome 2018-02-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV000774930 SCV001185748 pathogenic Hereditary cancer-predisposing syndrome 2019-09-06 criteria provided, single submitter clinical testing The p.Q1756* pathogenic mutation (also known as c.5266C>T), located in coding exon 18 of the BRCA1 gene, results from a C to T substitution at nucleotide position 5266. This changes the amino acid from a glutamine to a stop codon within coding exon 18. This alteration has been seen in multiple individuals referred for BRCA1/2 genetic testing (Stoppa-Lyonnet D et al. Am. J. Hum. Genet. 1997 May;60:1021-30; Kang E et al. Breast Cancer Res. Treat. 2015 May;151:157-68; Kwong A et al. J. Med. Genet. 2016 Jan;53:15-23; Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). One functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature. 2018 10;562:217-222). Of note, this alteration is also designated as 5385C>T 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 or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae RCV001385497 SCV001585375 pathogenic Hereditary breast and ovarian cancer syndrome 2019-06-25 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln1756*) in the BRCA1 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 families affected with increased risk of breast and ovarian cancers (PMID: 29446198). ClinVar contains an entry for this variant (Variation ID: 55490). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Brotman Baty Institute,University of Washington RCV000257437 SCV001242976 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000657590 SCV001552331 uncertain significance not provided no assertion criteria provided clinical testing

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