chr2-214809491-C-G
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_000465.4(BARD1):c.79G>C(p.Glu27Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000305 in 1,607,696 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E27A) 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 -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BARD1 | NM_000465.4 | c.79G>C | p.Glu27Gln | missense_variant | 1/11 | ENST00000260947.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BARD1 | ENST00000260947.9 | c.79G>C | p.Glu27Gln | missense_variant | 1/11 | 1 | NM_000465.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152212Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000128 AC: 3AN: 233664Hom.: 0 AF XY: 0.00000777 AC XY: 1AN XY: 128782
GnomAD4 exome AF: 0.0000316 AC: 46AN: 1455484Hom.: 0 Cov.: 76 AF XY: 0.0000332 AC XY: 24AN XY: 723828
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152212Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1AN XY: 74360
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 13, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 11, 2017 | This variant is denoted BARD1 c.79G>C at the cDNA level, p.Glu27Gln (E27Q) at the protein level, and results in the change of a Glutamic Acid to a Glutamine (GAA>CAA). This variant was shown through in vitro functional studies to have homology directed DNA repair activity and BARD1 protein expression similar to that of wild-type (Lee 2015). BARD1 Glu27Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Glutamic Acid and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. BARD1 Glu27Gln is located in the BRCA1 interaction domain (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 Glu27Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
Familial cancer of breast Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 27 of the BARD1 protein (p.Glu27Gln). This variant is present in population databases (rs587780037, gnomAD 0.009%). This missense change has been observed in individual(s) with B-cell acute lymphoblastic leukemia (PMID: 36187937). ClinVar contains an entry for this variant (Variation ID: 127748). 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 does not substantially affect BARD1 function (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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 20, 2023 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 11, 2023 | This missense variant replaces glutamic acid with glutamine at codon 27 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). The mutant protein has been reported to be functional in a homology-directed DNA repair assay (PMID: 26350354). This variant has not been reported in individuals affected with hereditary cancer in the literature. In a large breast cancer case-control study, this variant has been observed in 0/60466 cases and 1/53460 controls (PMID: 33471991 - Leiden Open Variation Database DB-ID BARD1_000492). This variant has been identified in 3/233664 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 18, 2018 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 20, 2020 | DNA sequence analysis of the BARD1 gene demonstrated a sequence change, c.79G>C, in exon 1 that results in an amino acid change, p.Glu27Gln. This sequence change does not appear to have been previously described in patients with BARD1-related disorders and been described in the gnomAD database with a low population frequency of 0.0013% (dbSNP rs587780037). The p.Glu27Gln change affects a poorly conserved amino acid residue located in a domain of the BARD1 protein that is not known to be functional. The p.Glu27Gln substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Glu27Gln change remains unknown at this time. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at