ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5089T>C (p.Cys1697Arg)

dbSNP: rs80356993
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Total submissions: 11
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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) RCV000077594 SCV001161642 pathogenic Breast-ovarian cancer, familial, susceptibility to, 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 5 based on posterior probability = 0.999867
Ambry Genetics RCV000163799 SCV000214380 likely pathogenic Hereditary cancer-predisposing syndrome 2015-09-24 criteria provided, single submitter clinical testing The p.C1697R variant (also known as c.5089T>C), located in coding exon 16 of the BRCA1 gene, results from a T to C substitution at nucleotide position 5089. The cysteine at codon 1697 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration has been identified in several Scandinavian breast/ovarian cancer kindreds and has not been reported in control populations (<span style="background-color:initial">Malander S, Eur. J. Cancer 2004 Feb; 40(3):422-8; Thomassen M, Acta Oncol 2008; 47(4):772-7; <span style="background-color:initial">Bergthorsson JT, J. Med. Genet. 2001 Jun; 38(6):361-8)<span style="background-color:initial">. Structural modeling and functional assays evaluating proteolytic degradation, protein stability, transcriptional activation, peptide binding ability have suggested that this alteration results in reduced or loss of wild type function (<span style="background-color:initial">Vallon-Christersson J, Hum. Mol. Genet. 2001 Feb; 10(4):353-60; <span style="background-color:initial">Williams RS, J. Biol. Chem. 2003 Dec; 278(52):53007-16; <span style="background-color:initial">Glover JN, Fam. Cancer 2006 ; 5(1):89-93). <span style="background-color:initial">Multifactorial and computational likelihood models predict this variant to be deleterious (<span style="background-color:initial">Karchin R, PLoS Comput. Biol. 2007 Feb; 3(2):e26; <span style="background-color:initial">Iversen ES, Cancer Epidemiol. Biomarkers Prev. 2011 Jun; 20(6):1078-88). Of note, this alteration is also designated as 5208T>C in published literature. Internal structural analysis predicts that this substitution will disrupt the structure of BRCA2 such that it will impact the protein-protein interaction interfaces (Ambry internal data; Clapperton JA et al. Nat. Struct. Mol. Biol., 2004 Jun;11:512-8<span style="background-color:initial">). Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be possibly damaging and deleterious by PolyPhen and SIFT in silico<span style="background-color:initial"> analyses, respectively. <span style="background-color:initial">Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001284299 SCV001470009 likely pathogenic not provided 2019-12-01 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Invitae RCV001378925 SCV001576625 likely pathogenic Hereditary breast ovarian cancer syndrome 2021-08-12 criteria provided, single submitter clinical testing
GeneDx RCV001284299 SCV002512833 pathogenic not provided 2022-04-29 criteria provided, single submitter clinical testing Observed in individuals with BRCA1-related cancers (Bergthorsson 2001, Vallon-Christersson 2001, Malander 2004, Cruger 2005, Thomassen 2008); Published functional studies demonstrate a damaging effect: impaired transcriptional activity, binding capacity, protein folding and stability, homologous recombination, cell survival, nuclear localization, and protein expression (Vallon-Christersson 2001, Glover 2006, Lee 2010, Anantha 2017, Findlay 2018, Petitalot 2019, Fernandes 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Also known as 5208T>C; This variant is associated with the following publications: (PMID: 15133502, 30209399, 21447777, 17305420, 11389159, 20516115, 30415210, 30765603, 28398198, 16528612, 14534301, 31131967, 30257991, 18465347, 14746861, 31409081, 24729269, 10946236, 28277317, 24845084, 11157798, 20423312, 24772314, 28781887, 16098011, 32341426, 33087888, 31742824, 25348405)
Sharing Clinical Reports Project (SCRP) RCV000077594 SCV000109397 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2013-04-19 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077594 SCV000145307 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 1999-04-12 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000077594 SCV001242097 not provided Breast-ovarian cancer, familial, susceptibility to, 1 no assertion provided in vitro
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357130 SCV001552490 likely pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Cys1697Arg variant was identified in 9 of 1204 proband chromosomes (frequency 0.007) from Danish and Swedish individuals or families with hereditary breast and/or ovarian cancer, bilateral or multifocal breast cancer, or invasive epithelial ovarian carcinoma, and was not identified in 360 control chromosomes from healthy individuals (Malander_2004_14746861, Thomassen_2008_18465347, Bergthorsson_2001_11389159). It was not identified in the GeneInsight-COGR, COSMIC, MutDB, ARUP Laboratories, or Zhejiang Colon Cancer databases. The variant was identified in dbSNP (ID: rs80356993) as “With Likely pathogenic, Uncertain significance allele”, ClinVar and Clinvitae (1x classified as likely pathogenic by Ambry Genetics; 2x classified as uncertain significance by SCRP and BIC; 1x not classified by Invitae), LOVD 3.0 (10x with multiple functional study citations), UMD-LSDB (predicted to be pathogenic), BIC Database (3 samples recorded with clinical importance classified as unknown) databases. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). Multiple functional studies have investigated the effect of this variant. Limited proteolysis to determine stability of the protein fold using in vitro transcribed/translated material noted that the C1697R mutant showed a particularly low protein expression level (Lee_2010_20516115). Using yeast and mammalian-based transcription assays this variant displayed loss of transcriptional activity, suggesting that it represents a disease-associated mutation, in agreement with pedigree analysis (Vallon-Christersson_2001_11157798). This study notes that C1697R is a dramatic amino acid substitution, from a non-polar residue capable of forming disulfide linkages to a positively charged residue, located in a critical alpha-helix based on the structure of XRCC1 BRCT, and that this variant was found to segregate with disease in 1 family in the study and 3 other breast cancer patients from another study (Bergthorsson_2001_11389159). In a protease-based assay, substitution of arginine showed increased sensitivity to chymotryptic cleavage at 20°C, suggesting that destabilizing effects, rather than the introduction of a new trypsin cleavage site, are responsible for the protease sensitivity (Williams_2003_14534301). A peptide-binding assay determined that the variant has a severe folding effect (Williams_2004_15133503). In a study which screened DNA using SSCA and PTT, the BRCA1 construct containing Arg1697 was not able to activate transcription in this system, supporting the classification of C1697R as a pathogenic mutation (Bergthorsson_2001_11389159). The p.Cys1697Arg residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV001284299 SCV001741498 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV001284299 SCV001905927 likely pathogenic not provided no assertion criteria provided clinical testing

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