ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4520G>C (p.Arg1507Thr) (rs80357470)

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Total submissions: 9
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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) RCV000112353 SCV001161594 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 = 0.000442
Invitae RCV000048585 SCV000076598 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-10-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with threonine at codon 1507 of the BRCA1 protein (p.Arg1507Thr). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and threonine. This variant is present in population databases (rs80357470, ExAC 0.01%). This variant has been observed in an individual affected with prostate cancer (PMID: 29368341). ClinVar contains an entry for this variant (Variation ID: 41825). This variant has been reported not to substantially affect BRCA1 protein function (PMID: 30765603, 28781887). In addition, based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a low probability of being pathogenic (PMID: 31131967). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000129298 SCV000184059 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-15 criteria provided, single submitter clinical testing The p.R1507T variant (also known as c.4520G>C), located in coding exon 13 of the BRCA1 gene, results from a G to C substitution at nucleotide position 4520. The arginine at codon 1507 is replaced by threonine, an amino acid with similar properties. In one study, where both SIFT and Ancestral Sequence methods were applied to predict BRCA1 deleterious mutations from variants reported in the BIC database, this variant was found to be deleterious (Pavlicek A et al. Hum. Mol. Genet. 2004 Nov; 13(22):2737-51). Using an in vivo prediction tool, this variant was predicted to create additional kinase binding sites (Tram E et al. PLoS ONE 2013; 8(5):e62468). However, other in silico prediction models have predicted conflicting results for the pathogenicity of this variant (Martelotto LG et al. Genome Biol. 2014; 15(10):484). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000034751 SCV000569833 uncertain significance not provided 2016-11-01 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4520G>C at the cDNA level, p.Arg1507Thr (R1507T) at the protein level, and results in the change of an Arginine to a Threonine (AGG>ACG). Using alternate nomenclature, this variant would be defined as BRCA1 4639G>C. This variant was observed in 1/572 individuals with atherosclerosis, with no specific information about cancer history (Johnston 2012). BRCA1 Arg1507Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Threonine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Arg1507Thr occurs at a position that is not conserved and is located in a region known for interaction with multiple proteins (Narod 2004, Clark 2012). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Arg1507Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Health, Inc RCV000129298 SCV000683191 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-26 criteria provided, single submitter clinical testing This missense variant replaces arginine with threonine at codon 1507 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals and families affected with breast and/or ovarian cancer (PMID: 16267036) and prostate cancer (PMID: 29368341). This variant has been reported as benign by a multifactorial analysis based in part on tumor pathology and family history likelihood ratios (PMID: 31131967). This variant has been identified in 7/251338 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 RCV001175600 SCV001339247 uncertain significance not specified 2020-03-03 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4520G>C (p.Arg1507Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251338 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4520G>C has been reported in the literature in individuals affected with prostate cancer (IsaacssonVelho_2018) and in at least one individual undergoing genetic testing for Hereditary Breast and Ovarian Cancer (Judkins_2005). The variant was also reported in an individual from a cohort selected for atherosclerosis phenotypes (Johnston_2012). These reports do not provide strong evidence for causality and thus 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. No damaging effects for the variant were observed on transcriptional activity as measured in assays using yeast cells (Woods_2016, Fernandes_2019). Four clinical diagnostic laboratories and one expert panel have submitted clinical significance assesments for this variant to ClinVar (evaluation after 2014) and cite the variant as uncertain significance (n=4) and benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Research and Development, ARUP Laboratories RCV001659945 SCV001878372 benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034751 SCV000043158 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112353 SCV000145113 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing

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