rs786202232
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_000465.4(BARD1):c.1940A>G(p.Gln647Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,613,932 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 (★★).
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.1940A>G | p.Gln647Arg | missense_variant | 10/11 | ENST00000260947.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BARD1 | ENST00000260947.9 | c.1940A>G | p.Gln647Arg | missense_variant | 10/11 | 1 | NM_000465.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152188Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251374Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135858
GnomAD4 exome AF: 0.0000253 AC: 37AN: 1461744Hom.: 0 Cov.: 30 AF XY: 0.0000220 AC XY: 16AN XY: 727166
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152188Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74344
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 01, 2021 | This missense variant replaces glutamine with arginine at codon 647 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 been reported in an individual undergoing genetic testing because of personal or family history of cancer (PMID: 27878467). This variant has been identified in 1/251374 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 | Dec 20, 2023 | The p.Q647R variant (also known as c.1940A>G), located in coding exon 10 of the BARD1 gene, results from an A to G substitution at nucleotide position 1940. The glutamine at codon 647 is replaced by arginine, an amino acid with highly similar properties. This alteration has been detected in a cohort of 122 patients who underwent multi-gene panel testing for hereditary cancer after having previously tested negative for mutations in BRCA1 and BRCA2 (Yadav S et al. Fam Cancer, 2017 07;16:319-328). Additionally, this variant was reported in 0/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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:2
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 23, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 17, 2023 | This variant is present in population databases (rs786202232, gnomAD 0.0009%). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 647 of the BARD1 protein (p.Gln647Arg). ClinVar contains an entry for this variant (Variation ID: 185508). This missense change has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 27878467). 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at