ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5531T>G (p.Leu1844Arg) (rs80357323)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 12
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000083221 SCV001161503 benign Breast-ovarian cancer, familial 1 2019-06-18 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000321
Ambry Genetics RCV000131565 SCV000186569 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-14 criteria provided, single submitter clinical testing
GeneDx RCV000586607 SCV000209994 uncertain significance not provided 2018-07-24 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5531T>G at the cDNA level, p.Leu1844Arg (L1844R) at the protein level, and results in the change of a Leucine to an Arginine (CTC>CGC). This variant, also known as BRCA1 5650T>G using alternate nomenclature, was reported as having an uncertain clinical effect based on biochemical and cell-based transcriptional assays (Lee 2010). This variant has been observed in at least one HBOC family and at least one individual with breast cancer (Peixoto 2014, Dean 2015). BRCA1 Leu1844Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the BRCT2 domain and a region known to interact with multiple proteins (UniProt, Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Leu1844Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000586607 SCV000228064 uncertain significance not provided 2015-06-09 criteria provided, single submitter clinical testing
Counsyl RCV000083221 SCV000489614 uncertain significance Breast-ovarian cancer, familial 1 2016-11-02 criteria provided, single submitter clinical testing
Color RCV000131565 SCV000683333 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000855577 SCV000699270 uncertain significance not specified 2019-08-30 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5531T>G (p.Leu1844Arg) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250824 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5531T>G has been reported in the literature in individuals affected with Breast and Ovarian Cancer (Dean_2015, Peixoto_2014, Judkins_2005) and in an individual with Sebacious Carcinoma in whom a different somatic etiology, namely a somatic inactivation of MSH2 and MSH6 genes was reported (Wield_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Several publications report experimental evidence evaluating an impact on protein function by transcriptional activation assays (example (Lee_2010, Woods_2016, Fernandes_2019) . These results have consistently demonstrated no damaging effect of this variant. Eight clinical diagnostic laboratories including ours have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories have classified the variant as uncertain significance using the same overlapping literature evidence. Based on the evidence outlined above, despite strong functional evidence supporting a likely benign outcome, due to a lack of clinical evidence corroborating the functional evidence, the variant was classified as VUS-possibly benign.
Mendelics RCV000709463 SCV000839207 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586607 SCV001133641 uncertain significance not provided 2018-09-17 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000083221 SCV000115295 likely benign Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000083221 SCV000145568 not provided Breast-ovarian cancer, familial 1 no assertion provided clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000586607 SCV000778731 uncertain significance not provided 2017-11-02 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.