ClinVar Miner

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

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Total submissions: 7
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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) 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 2014-05-21 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.5053A>G at the cDNA level, p.Thr1685Ala (T1685A) at the protein level, and results in the change of a Threonine to an Alanine (ACT>GCT). This variant has been classified as deleterious or likely deleterious based on interspecific sequence variation (Abkevich 2004), structural based assessment (Mirkovic 2004), multiple computational algorithms (Karchin 2007), and functional assays (Lee 2010). The mutation was strongly predicted by Lindor et al. (2012) to be deleterious based on tumor pathology, clinical histories, family studies and co-occurrence with deleterious variants. BRCA1 Thr1685Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Threonine and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Thr1685Ala occurs at a position that is well conserved across species and is located in the BRCT1 domain (UniProt). In addition, In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the current information, we consider this variant to be pathogenic.
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
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

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