ClinVar Miner

Submissions for variant NM_000465.4(BARD1):c.160A>G (p.Thr54Ala) (rs200254470)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129266 SCV000184026 likely benign Hereditary cancer-predisposing syndrome 2018-11-16 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s);Other data supporting benign classification
GeneDx RCV000236190 SCV000292756 uncertain significance not provided 2018-11-20 criteria provided, single submitter clinical testing This variant is denoted BARD1 c.160A>G at the cDNA level, p.Thr54Ala (T54A) at the protein level, and results in the change of a Threonine to an Alanine (ACT>GCT). This variant was found to have DNA repair activity similar to wildtype cells in a homology-directed repair (HDR) assay (Lee 2015). BARD1 Thr54Ala was observed at an allele frequency of 0.02% (18/111,406) in individuals of European (Non-Finnish) ancestry in large population cohorts (Lek 2016). Since Threonine and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BARD1 Thr54Ala is located in the RING domain of the BRCA1 interaction region (Fox 2008). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether BARD1 Thr54Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000473762 SCV000545619 uncertain significance Familial cancer of breast 2020-10-21 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 54 of the BARD1 protein (p.Thr54Ala). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs200254470, ExAC 0.01%). This variant has been reported in an individual affected with breast cancer (PMID: 20030863). ClinVar contains an entry for this variant (Variation ID: 140974). An experimental study has shown that this variant does not disrupt BARD1 homology directed repair activity in vitro (PMID: 26350354). 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.
GeneKor MSA RCV000129266 SCV000821889 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000473762 SCV000837985 uncertain significance Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129266 SCV000910749 likely benign Hereditary cancer-predisposing syndrome 2016-04-22 criteria provided, single submitter clinical testing

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