ClinVar Miner

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

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131565 SCV000186569 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-14 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000083221 SCV000145568 not provided Breast-ovarian cancer, familial 1 no assertion provided clinical testing
Color RCV000131565 SCV000683333 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-14 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
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000586607 SCV000228064 uncertain significance not provided 2015-06-09 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.
Integrated Genetics/Laboratory Corporation of America RCV000586607 SCV000699270 uncertain significance not provided 2017-06-29 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.5531T>G (p.Leu1844Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide located in the BRCT domain (Interpro). 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not available). Multiple in silico studies resulted in contradictory results, predicting this variant to be neutral, deleterious or a VUS (Carvalho_PLOS One_2014, Karchin_BRCA2_PLOS_2007, Iversen_Cancer Epidemiol Biomarkers Prev_2011). One functional study determined this variant to be uncertain due to conflicting results of structural stability, binding activity, and specificity assays (Lee_CR_2010). The variant of interest has been found in a large, broad control population, ExAC in 3/121266 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). This variant was reported in breast cancer patients without strong evidence for causality (Dean_GigaScience_2015, Peixoto_BRCA1&2_Clin Genet_2014). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS, until more definitive clinical and functional studies become available.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000586607 SCV000778731 uncertain significance not provided 2017-11-02 no assertion criteria provided clinical testing
Mendelics RCV000709463 SCV000839207 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 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

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