rs141351035
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting
The NM_000465.4(BARD1):c.1084T>G(p.Cys362Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000908 in 1,541,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. C362S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000465.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BARD1 | NM_000465.4 | c.1084T>G | p.Cys362Gly | missense_variant | 4/11 | ENST00000260947.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BARD1 | ENST00000260947.9 | c.1084T>G | p.Cys362Gly | missense_variant | 4/11 | 1 | NM_000465.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000626 AC: 9AN: 143754Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251302Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135822
GnomAD4 exome AF: 0.00000358 AC: 5AN: 1397628Hom.: 0 Cov.: 35 AF XY: 0.00000288 AC XY: 2AN XY: 693410
GnomAD4 genome ? AF: 0.0000626 AC: 9AN: 143754Hom.: 0 Cov.: 32 AF XY: 0.0000570 AC XY: 4AN XY: 70224
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 16, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26580448, 36187937) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 30, 2023 | In the published literature, this variant has been reported in a an affected individual with retinoblastoma (PMID: 26580448 (2015)). The frequency of this variant in the general population, 0.00028 (7/24962 chromosomes in African/African American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 27, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 18, 2022 | The p.C362G variant (also known as c.1084T>G), located in coding exon 4 of the BARD1 gene, results from a T to G substitution at nucleotide position 1084. The cysteine at codon 362 is replaced by glycine, an amino acid with highly dissimilar properties. This variant has been reported in 1/1120 pediatric cancer patients, who underwent whole genome sequencing and/or whole exome sequencing; this patient was diagnosed with retinoblastoma (Zhang J et al. N. Engl. J. Med., 2015 Dec;373:2336-2346). This amino acid position is not 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. - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 362 of the BARD1 protein (p.Cys362Gly). This variant is present in population databases (rs141351035, gnomAD 0.03%). This missense change has been observed in individual(s) with retinoblastoma (PMID: 36187937). ClinVar contains an entry for this variant (Variation ID: 184930). 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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at