ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5053A>G (p.Thr1685Ala) (rs80356890)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000112475 SCV000244379 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
Invitae RCV000048749 SCV000076762 pathogenic Hereditary breast and ovarian cancer syndrome 2020-02-21 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 1685 of the BRCA1 protein (p.Thr1685Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast or ovarian cancer (PMID: 11802209), and individuals in the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 55364). Experimental studies have shown that this missense change has a strong effect on BRCA1 transcriptional activity, peptide binding specificity and structural stability (PMID: 20516115, 27272900). A different missense substitution at this codon (p.Thr1685Ile) is reported to be deleterious (PMID: 20516115, 15689452, 17924331, 15172985). This suggests that the threonine residue is critical for BRCA1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000212192 SCV000210194 pathogenic not provided 2021-06-14 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect with respect to: stability, binding activity and specificity, transcription activity, and protease sensitivity (Lee 2010, Thouvenot 2016, Woods 2016, Findlay 2018, Fernandes 2019); Multifactorial studies suggest this variant is associated with breast and ovarian cancer (Lindor 2012); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Meindl 2002, Rebbeck 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 5172A>G; Not observed at significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 17305420, 17924331, 15235020, 29446198, 11802209, 24772314, 9974970, 11301010, 10220405, 24389207, 9738006, 9159119, 9926942, 10196224, 9811458, 30765603, 30209399, 20516115, 27272900, 28781887, 21990134, 27535533, 31131967, 15172985, 33087888)
Ambry Genetics RCV000163024 SCV000213512 pathogenic Hereditary cancer-predisposing syndrome 2017-06-09 criteria provided, single submitter clinical testing The p.T1685A pathogenic mutation (also known as c.5053A>G<span style="background-color:initial">), located in coding exon 15 of the BRCA1<span style="background-color:initial"> gene, results from an A to G substitution at nucleotide position 5053. The threonine at codon 1685 is replaced by alanine, an amino acid with similar properties. <span style="background-color:initial">This alteration has been classified as pathogenic (p>0.99) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Easton D et al. Am J Hum Genet<span style="background-color:initial">. 2007;81:873-883; Tavtigian SV et al. Hum Mutat.<span style="background-color:initial"> 2008 Nov;29(11):1342-54; Lindor NM et al. Hum Mutat<span style="background-color:initial">. 2012 Jan;33(1):8-21). Another functional study demonstrated large defects in protein stability, phosphopeptide binding activity and specificity, and transcriptional activity of the BRCT domain (Lee MS et al. Cancer Res. 2010 Jun;70(12):4880-90).<span style="background-color:initial"> Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000112475 SCV000326121 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001663985 SCV001878409 pathogenic Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Breast Cancer Information Core (BIC) (BRCA1) RCV000112475 SCV000145276 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000112475 SCV001237500 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.