ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4222C>T (p.Gln1408Ter) (rs80356989)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 16
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131888 SCV000186943 pathogenic Hereditary cancer-predisposing syndrome 2016-08-05 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) RCV000077568 SCV000145036 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Color RCV000131888 SCV000683164 pathogenic Hereditary cancer-predisposing syndrome 2017-06-12 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077568 SCV000325901 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000077568 SCV000488183 pathogenic Breast-ovarian cancer, familial 1 2016-01-19 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000236506 SCV000225649 pathogenic not provided 2014-09-11 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000077568 SCV000300094 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 RCV000236506 SCV000292518 pathogenic not provided 2018-11-27 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.4222C>T at the cDNA level and p.Gln1408Ter (Q1408X) 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 reported as BRCA1 4341C>T using alternate nomenclature, has been reported in individuals with familial and early-onset breast and/or ovarian cancer (Shattuck-Eidens 1997, Dong 1998, Borg 2010). We consider this variant to be pathogenic.
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785414 SCV000923986 pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
Integrated Genetics/Laboratory Corporation of America RCV000214098 SCV000699123 pathogenic Hereditary breast and ovarian cancer syndrome 2017-07-27 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.4222C>T (p.Gln1408X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 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. c.4243delG, p.Glu1415fsX4; c.4258C>T, p.Gln1420X; c.4327C>T, p.Arg1443X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/121376 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). The variant has been reported in numerous affected individuals in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000214098 SCV000076505 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln1408*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs80356989, ExAC 0.001%). This variant has been observed in individuals affected with breast and/or ovarian cancer (PMID: 9333265, 9760198, 20104584, 22009639). This variant is also known as c.4341C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 55145). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000214098 SCV000271318 pathogenic Hereditary breast and ovarian cancer syndrome 2015-03-23 criteria provided, single submitter clinical testing The p.Gln1408X variant in BRCA1 has been previously reported in 2 women with bre ast and/or ovarian cancer and was found to segregate with disease in 6 affected members of 1 family with BRCA1-associated cancer, including 2 obligate carriers (Shattuck-Eidens 1997, Dong 1998). It has not been identified in large populatio n studies. This nonsense variant leads to a premature termination codon at posit ion 1408, which is predicted to lead to a truncated or absent protein. Heterozyg ous loss of BRCA1 function is an established disease mechanism in hereditary bre ast and ovarian cancer (HBOC). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon th e predicted impact to the protein, absence from controls, and segregation studie s.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000077568 SCV000296449 pathogenic Breast-ovarian cancer, familial 1 2016-05-06 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000236506 SCV000888911 pathogenic not provided 2016-05-06 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000214098 SCV000587383 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000077568 SCV000109370 pathogenic Breast-ovarian cancer, familial 1 2011-03-31 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.