2-214728810-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP3BS2_Supporting
The NM_000465.4(BARD1):āc.2200A>Gā(p.Thr734Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T734I) has been classified as Uncertain significance.
Frequency
Consequence
NM_000465.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BARD1 | NM_000465.4 | c.2200A>G | p.Thr734Ala | missense_variant | 11/11 | ENST00000260947.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BARD1 | ENST00000260947.9 | c.2200A>G | p.Thr734Ala | missense_variant | 11/11 | 1 | NM_000465.4 | P2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461888Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727244
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2023 | This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 734 of the BARD1 protein (p.Thr734Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BARD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 481364). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects BARD1 function (PMID: 16651405, 18842000, 20379136). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 12, 2023 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 21, 2024 | The p.T734A variant (also known as c.2200A>G), located in coding exon 11 of the BARD1 gene, results from an A to G substitution at nucleotide position 2200. The threonine at codon 734 is replaced by alanine, an amino acid with similar properties. This alteration has been demonstrated to be defective in the inhibition of mRNA 3' cleavage and degradation of RNAP II in response to DNA damage. Furthermore, UV-induced activation of deadenylation decreased by almost 50% in nuclear extracts from cells expressing p.T734A compared to wild type (Kim HS et al. Cancer Res. 2006 May; 66(9):4561-5; Cevher MA et al. EMBO J. 2010 May; 29(10):1674-87). Structural analysis shows that this residue is buried within a BRCT repeat, suggesting that loss of function in p.T734A may be due to its negative effects on the integrity of the BRCT repeat structure rather than loss of a phosphorylation site (Edwards RA et al. Biochemistry. 2008 Nov; 47(44):11446-56), although direct evidence is unavailable. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 17, 2019 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 17, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect: defective RNAP II degradation and mRNA cleavage, reduced UV-induced activation of deadenylation, and loss of UV-induced phosphorylation of BARD1 (Kim et al., 2006; Cevher et al., 2010); This variant is associated with the following publications: (PMID: 17550235, 18842000, 16651405, 20379136) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at