ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4484G>C (p.Arg1495Thr) (rs80357389)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236135 SCV000292747 pathogenic not provided 2015-10-29 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4484G>C at the cDNA level, p.Arg1495Thr (R1495T) 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 4603G>C. This variant was observed in an mRNA in-vitro splicing assay to create two aberrant transcripts, both of which lead to deleterious protein function, one skipping exon 14 and the other skipping exons 14-15 (Whiley 2014). BRCA1 Arg1495Thr 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 Arginine and Threonine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Arg1495Thr occurs at a position that is not conserved and is located within the SCD domain, the DNA binding domain and within a region known to interact with multiple other proteins (Narod 2004, Paul 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available information, we consider BRCA1 Arg1495Thr to be a pathogenic variant.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000258262 SCV000325978 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Color RCV000580649 SCV000683188 pathogenic Hereditary cancer-predisposing syndrome 2015-11-19 criteria provided, single submitter clinical testing

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