ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5095C>T (p.Arg1699Trp) (rs55770810)

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Total submissions: 23
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131821 SCV000186876 pathogenic Hereditary cancer-predisposing syndrome 2018-01-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Baylor Genetics RCV000457515 SCV000540931 pathogenic Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Bioinformatics dept.,Datar Cancer Genetics Limited, India RCV000077595 SCV000584018 pathogenic Breast-ovarian cancer, familial 1 2017-06-20 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077595 SCV000145309 pathogenic Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000148390 SCV000190089 pathogenic Breast and colorectal cancer 2014-06-01 no assertion criteria provided research
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077595 SCV000326154 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000077595 SCV000744600 pathogenic Breast-ovarian cancer, familial 1 2015-09-21 criteria provided, single submitter clinical testing
Department of Medical Genetics,Oslo University Hospital RCV000077595 SCV000564374 pathogenic Breast-ovarian cancer, familial 1 2015-10-20 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000077595 SCV000733599 pathogenic Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000077595 SCV000244382 pathogenic Breast-ovarian cancer, familial 1 2015-08-10 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 = 1
GeneDx RCV000159999 SCV000210197 pathogenic not provided 2018-07-11 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5095C>T at the cDNA level, p.Arg1699Trp (R1699W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). Using alternate nomenclature, this pathogenic variant would be defined as BRCA1 5214C>T and has been reported in many breast/ovarian cancer families (Rhiem 2007, Spurdle 2012, Laraqui 2013). In addition, BRCA1 Arg1699Trp has been documented in the compound heterozygous state in a woman with multiple congenital anomalies and a cellular phenotype consistent with a Fanconi anemia-like disorder and breast cancer at age 23 (Sawyer 2015). Although an early functional study suggested neutrality (Vallon-Christersson 2001), later functional studies, including those looking at homologous recombination and binding, were unequivocal in showing that this variant impairs function (Coquelle 2011, Bouwman 2013). Furthermore, multifactorial models based on tumor pathology, clinical histories, family studies and co-occurrence with deleterious variants predict this variant to be deleterious (Lindor 2012, Spurdle 2012). BRCA1 Arg1699Trp was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Arginine and Tryptophan differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Arg1699Trp occurs at a position that is conserved and is located in the BRCT1 domain and a region known to interact with multiple other proteins (Narod 2004, Paul 2014). In silico analyses predict that this pathogenic variant is probably damaging to protein structure and function. Based on all available information, we consider this variant to be pathogenic.
GeneKor MSA RCV000239322 SCV000296777 pathogenic Ovarian cancer 2017-11-01 criteria provided, single submitter clinical testing
Genologica Medica RCV000077595 SCV000577934 pathogenic Breast-ovarian cancer, familial 1 2017-01-01 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000077595 SCV000743380 pathogenic Breast-ovarian cancer, familial 1 2017-07-28 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000077595 SCV000993551 pathogenic Breast-ovarian cancer, familial 1 2019-01-22 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000048789 SCV000918722 pathogenic Hereditary breast and ovarian cancer syndrome 2017-11-16 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.5095C>T (p.Arg1699Trp) variant involves the alteration of a conserved nucleotide located in the BCRT domain (InterPro). 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 6/246572 control chromosomes at a frequency of 0.0000243, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). This variant is widely known as a recurrent pathogenic variant found in several HBOC families, including one patient with potential de novo/germline mosaicism transmission (Antonucci_2016). Patient data, functional data, and data from multifactorial probability based model consistently suggests for a pathogenic outcome. The residue p.Arg1699 is a critical residue that plays an important role in phosphopeptide recognition and functional assays have shown that the variant significantly impairs transcriptional activity in mammalian cell line, is unable to fully functionally complement BRCA1-deficient mouse embryonic stem cells, and leads to defective phosphopeptide binding (Vallon-Christersson_2001, Coquelle_2011, and Bouwman_2013). The residue p.Arg1699 is also a mutational hot-spot and two other likely pathogenic variants p.Arg1699Gln and p.Arg1699Leu have been reported in it. In addition, numerous clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000048789 SCV000076802 pathogenic Hereditary breast and ovarian cancer syndrome 2018-11-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1699 of the BRCA1 protein (p.Arg1699Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs55770810, ExAC 0.01%). This variant has been reported in individuals with breast and/or ovarian cancer (PMID: 22889855, 21324516, 21356067), and was shown to segregate with breast/ovarian cancer in two families (PMID: 11157798, 17574969). It was also found in trans with a pathogenic BRCA1 variant in an individual affected with Fanconi anemia (PMID: 25472942). ClinVar contains an entry for this variant (Variation ID: 55396). Experimental studies have shown that this missense change disrupts BRCA1 binding ability and transcriptional activity (PMID: 21473589, 20516115, 17308087, 23867111). Also, a multifactorial likelihood algorithm using genetic, in silico, and statistical data has determined that this variant has a very high probability of being deleterious (PMID: 17924331, 21990134). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000585864 SCV000693739 pathogenic FANCONI ANEMIA, COMPLEMENTATION GROUP S 2015-02-01 no assertion criteria provided literature only
OMIM RCV000077595 SCV000693740 pathogenic Breast-ovarian cancer, familial 1 2015-02-01 no assertion criteria provided literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000159999 SCV000605901 pathogenic not provided 2016-08-04 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000048789 SCV000587461 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000077595 SCV000109398 pathogenic Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
University of Washington Center for Mendelian Genomics,University of Washington RCV000191041 SCV000246115 pathogenic Fanconi anemia, complementation group A 2015-05-19 no assertion criteria provided research

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