rs587782548
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4_Moderate
The NM_000465.4(BARD1):c.1180A>G(p.Thr394Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,614,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T394I) 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 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BARD1 | NM_000465.4 | c.1180A>G | p.Thr394Ala | missense_variant | 4/11 | ENST00000260947.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BARD1 | ENST00000260947.9 | c.1180A>G | p.Thr394Ala | missense_variant | 4/11 | 1 | NM_000465.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152218Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251122Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135704
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461822Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727204
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152218Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74360
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 29, 2023 | The p.T394A variant (also known as c.1180A>G), located in coding exon 4 of the BARD1 gene, results from an A to G substitution at nucleotide position 1180. The threonine at codon 394 is replaced by alanine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 13, 2021 | This missense variant replaces threonine with alanine at codon 394 of the BARD1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251122 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Familial cancer of breast Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 18, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 394 of the BARD1 protein (p.Thr394Ala). This variant is present in population databases (rs587782548, gnomAD 0.0009%). 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: 142564). 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 tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BARD1 function (PMID: 15855157). 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 08, 2016 | This variant is denoted BARD1 c.1180A>G at the cDNA level, p.Thr394Ala (T394A) at the protein level, and results in the change of a Threonine to an Alanine (ACA>GCA). A functional study revealed that this variant affects phosphorylation of BARD1, but the resulting impact on protein function is unclear (Choudhury 2005). BARD1 Thr394Ala 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. BARD1 Thr394Ala occurs at a position that is not conserved and is not located in a known functional domain (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BARD1 Thr394Ala is pathogenic or benign. We consider it to be a variant of uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at