ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4612C>T (p.Gln1538Ter) (rs80356992)

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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) RCV000077579 SCV000300145 pathogenic Breast-ovarian cancer, familial 1 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000048606 SCV000076619 pathogenic Hereditary breast and ovarian cancer syndrome 2019-10-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln1538*) 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 several individuals clinical features of hereditary breast and ovarian cancer syndrome (PMID: 9452076, 11920621, 25151137, 29446198,29470806). This variant is also known as 4731C>T in the literature. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077579 SCV000326009 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000420125 SCV000516967 pathogenic not provided 2018-08-13 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4612C>T at the cDNA level and p.Gln1538Ter (Q1538X) at the protein level. 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, also published as BRCA1 4731C>T using alternate nomenclature, has been observed in individuals with personal and/or family histories of breast and ovarian cancer (Tartaglini 1998, De Leon Matsuda 2002, Young 2009, Guan 2015) and is considered pathogenic.
Ambry Genetics RCV000510121 SCV000607974 pathogenic Hereditary cancer-predisposing syndrome 2018-08-27 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000420125 SCV001133591 pathogenic not provided 2019-05-02 criteria provided, single submitter clinical testing The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient in literature, and not found in general population data.
Integrated Genetics/Laboratory Corporation of America RCV000048606 SCV001338294 pathogenic Hereditary breast and ovarian cancer syndrome 2020-02-12 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4612C>T (p.Gln1538X) 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 251362 control chromosomes (gnomAD). c.4612C>T has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Rebbeck_2018, DeLeonMatsuda_2002, Singh_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. Six ClinVar submitters (evaluation after 2014) including one expert panel (ENIGMA) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color RCV000510121 SCV001348222 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077579 SCV000109382 pathogenic Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077579 SCV000145129 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing

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