ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5531T>G (p.Leu1844Arg) (rs80357323)

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Total submissions: 15
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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) 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 likely benign Hereditary cancer-predisposing syndrome 2020-04-07 criteria provided, single submitter clinical testing Intact protein function observed in appropriate functional assay(s);Other data supporting benign classification
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 Health, Inc RCV000131565 SCV000683333 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-26 criteria provided, single submitter clinical testing This missense variant replaces leucine with arginine at codon 1844 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported the variant protein to be functional in transcription activation assay in mammalian cells (PMID: 28781887, 20516115), in a haploid cell proliferation assay (PMID: 30209399), and in analysis of variant peptide stability and phosphopeptide binding specificity (PMID: 20516115). However, phosphopeptide binding was reported to be partially functional (PMID: 20516115). This variant has been reported in individuals with personal and family history of breast and ovarian cancer (PMID: 26543556, 24916970). A multifactorial analysis reported this variant to be benign driven by low odds ratio for family history of disease in carriers (PMID: 31131967). This variant has been identified in 5/250824 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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
Invitae RCV000709463 SCV001615582 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-25 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 Laboratories, Mayo Clinic RCV000586607 SCV000778731 uncertain significance not provided 2017-11-02 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000083221 SCV001243514 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358221 SCV001553895 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Leu1844Arg variant was identified in 2 of 2340 proband chromosomes (frequency: 0.0009) from individuals or families with breast and ovarian cancer (Dean 2015, Peixoto 2015). The variant identified in dbSNP (rs80357323) as “with uncertain significance allele”, ClinVar (interpreted as "uncertain significance by Ambry Genetics and 7 others and “likely benign" by SCRP), LOVD 3.0 (observed 3x) and UMD-LSDB (observed 2x). The variant was identified in control databases in 5 of 245,562 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 15,300 chromosomes (freq: 0.0001), Ashkenazi Jewish in 3 of 9820 chromosomes (freq: 0.0003), while the variant was not observed in the Other, Latino, European, East Asian, Finnish, and South Asian populations. The functional effect of the p.Leu1844Arg missense variant was assessed in a series of assays. Based on the nonconcordant results in binding, protease sensitivity and structural stability assays, the variant was classified as having an uncertain functional effect (Lee 2010). The p.Leu1844 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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