rs376256852
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_000465.4(BARD1):c.1793C>T(p.Thr598Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,613,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. T598A) has been classified as Likely benign.
Frequency
Consequence
NM_000465.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BARD1 | NM_000465.4 | c.1793C>T | p.Thr598Ile | missense_variant | 8/11 | ENST00000260947.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BARD1 | ENST00000260947.9 | c.1793C>T | p.Thr598Ile | missense_variant | 8/11 | 1 | NM_000465.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152090Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251232Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135768
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461772Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 727182
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 152090Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74286
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2023 | BARD1: PM2, BP4 - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 05, 2023 | 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 are inconclusive: intermediate effect on homology-directed repair activity (Adamovich et al., 2019); This variant is associated with the following publications: (PMID: 23056176, 32854451, 32726901, 17972171, 35650591, 17550235, 35402282, 35912549, 30925164) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 26, 2023 | - - |
Familial cancer of breast Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 598 of the BARD1 protein (p.Thr598Ile). This variant is present in population databases (rs376256852, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 17972171, 32854451). ClinVar contains an entry for this variant (Variation ID: 141929). 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 have shown that this missense change affects BARD1 function (PMID: 30925164). 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 | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | The p.T598I variant (also known as c.1793C>T), located in coding exon 8 of the BARD1 gene, results from a C to T substitution at nucleotide position 1793. The threonine at codon 598 is replaced by isoleucine, an amino acid with similar properties. This alteration was reported in a family with multiple cases of breast cancer; however, the alteration did not segregate with breast cancer in this family (Gorringe KL et al. Breast Cancer Res. Treat. 2008 Oct;111:505-9). In a homology-directed repair (HDR) assay, this alteration showed HDR activity just below the cutoff for proficiency (Adamovich AI et al. PLoS Genet., 2019 03;15:e1008049). In addition, in silico analysis showed Benign computational verdict based on 11 benign predictions from BayesDel_addAF, DANN, DEOGEN2, EIGEN, FATHMM-MKL and 6 more vs 2 pathogenic predictions from M-CAP and MutationAssessor and the position is not strongly conserved (GERP++ rejected substitutions = 2.18 is less than 5.5). This variant has an entry in ClinVar (141929) with 4 submissions, all of which list this variant as “uncertain significance”. Also, this variant was not found in gnomAD genomes. Therefore, this variant is classified as uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 15, 2024 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 23, 2023 | This missense variant replaces threonine with isoleucine at codon 598 of the BARD1 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has reported the mutant protein to exhibit partially reduced homology-directed DNA repair activity (PMID: 30925164). This variant has been reported in two individuals affected with breast cancer (PMID: 17972171, 32854451). In one of these families, this variant was not detected in other family members affected with breast cancer and colorectal cancer (PMID: 17972171). This variant has been identified in 2/251232 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 09, 2022 | The p.T598I variant (also known as c.1793C>T), located in coding exon 8 of the BARD1 gene, results from a C to T substitution at nucleotide position 1793. The threonine at codon 598 is replaced by isoleucine, an amino acid with similar properties. This alteration was reported in a family with multiple cases of breast cancer; however, the alteration did not segregate with breast cancer in this family (Gorringe KL et al. Breast Cancer Res Treat, 2008 Oct;111:505-9). This alteration was found to be functionally intermediate in a homology-directed DNA repair (HDR) assay (Adamovich AI et al. PLoS Genet, 2019 03;15:e1008049). In a multi-gene panel study of patients with bilateral breast cancer, this variant was observed in 1/139 cases (Fanale D et al. Cancers (Basel), 2020 Aug;12:). This amino acid position is poorly 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at