ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.1960A>T (p.Lys654Ter) (rs80357355)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131895 SCV000186950 pathogenic Hereditary cancer-predisposing syndrome 2017-08-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Breast Cancer Information Core (BIC) (BRCA1) RCV000031017 SCV000144259 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Color RCV000131895 SCV000905034 pathogenic Hereditary cancer-predisposing syndrome 2018-06-11 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031017 SCV000325201 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031017 SCV000487835 pathogenic Breast-ovarian cancer, familial 1 2015-11-23 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031017 SCV000299674 pathogenic Breast-ovarian cancer, familial 1 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000047658 SCV000210117 pathogenic not provided 2018-12-19 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.1960A>T at the cDNA level and p.Lys654Ter (K654X) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA1 2079A>T. The substitution creates a nonsense variant, which changes a Lysine to a premature stop codon (AAG>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 association with Hereditary Breast and Ovarian Cancer (John 2007, Weitzel 2013, Tung 2015, Rebbeck 2018) and is considered pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000203662 SCV000918779 pathogenic Hereditary breast and ovarian cancer syndrome 2018-09-13 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.1960A>T (p.Lys654X) 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 (e.g., p.Lys654fsX47 and p.Leu668fsX5). The variant was absent in 121332 control chromosomes (gnomAD). c.1960A>T has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer. 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. Seven ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000203662 SCV000075671 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys654*) 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 reported in studies of Hispanic cohorts in individuals with a personal or family history of breast and/or ovarian cancer (PMID: 16030099, 23233716, 18159056). ClinVar contains an entry for this variant (Variation ID: 37436). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000047658 SCV000296279 pathogenic not provided 2015-02-27 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031017 SCV000053610 pathogenic Breast-ovarian cancer, familial 1 2012-01-06 no assertion criteria provided clinical testing

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