ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.1616C>A (p.Thr539Lys) (rs80357374)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159953 SCV000210105 uncertain significance not provided 2014-02-07 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.1616C>A at the cDNA level, p.Thr539Lys (T539K) at the protein level, and results in the change of a Threonine to a Lysine (ACG>AAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Thr539Lys 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. This variant is a semi-conservative substitution in which a neutral polar amino acid is replaced with a positive polar one, altering a position that is highly variable throughout evolution and is not located in a known functional domain. In silico analyses are inconsistent with regard to the effect this variant may have on protein structure and function. Based on currently available information, we consider BRCA1 Thr539Lys to be a variant of uncertain significance.
Invitae RCV000685499 SCV000812982 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-06-13 criteria provided, single submitter clinical testing This sequence change replaces threonine with lysine at codon 539 of the BRCA1 protein (p.Thr539Lys). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 182132). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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