rs587782122
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting
The NM_000465.4(BARD1):c.1672T>C(p.Ser558Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,605,888 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. S558L) 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.1672T>C | p.Ser558Pro | missense_variant | 7/11 | ENST00000260947.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BARD1 | ENST00000260947.9 | c.1672T>C | p.Ser558Pro | missense_variant | 7/11 | 1 | NM_000465.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152212Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251258Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135804
GnomAD4 exome AF: 0.00000619 AC: 9AN: 1453676Hom.: 0 Cov.: 29 AF XY: 0.00000691 AC XY: 5AN XY: 723660
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152212Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74352
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 12, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 09, 2021 | This missense variant replaces serine with proline at codon 558 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). A functional study has shown that this variant protein leads to homology-directed DNA repair activity comparable to the wild-type protein in a mammalian cell-based assay (PMID: 30925164). This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 16825437). In a breast cancer case-control study, this variant was identified in 4/60462 cases and 2/53459 controls; OR=1.768 (95%CI 0.324 to 9.655); p-value=0.691 (PMID: 33471991 - Leiden Open Variation Database DB-ID BARD1_000193). This variant has been identified in 6/251258 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 | Apr 09, 2024 | The p.S558P variant (also known as c.1672T>C), located in coding exon 7 of the BARD1 gene, results from a T to C substitution at nucleotide position 1672. The serine at codon 558 is replaced by proline, an amino acid with similar properties. In one study, this variant was reported in four Norwegian families with breast or ovarian cancer (Karppinen SM et al. J. Med. Genet. 2006 Nov; 43(11):856-62). In a homology-directed repair (HDR) assay, this alteration showed HDR activity above the cutoff for proficiency (Adamovich AI et al. PLoS Genet. 2019 03;15(3):e1008049). 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. - |
Familial cancer of breast Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 08, 2023 | This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 558 of the BARD1 protein (p.Ser558Pro). This variant is present in population databases (rs587782122, gnomAD 0.004%). This missense change has been observed in individual(s) with breast or ovarian cancer (PMID: 16825437). ClinVar contains an entry for this variant (Variation ID: 141935). 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: 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 22, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies suggest no damaging effect: homology-directed repair similar to wild type (Adamovich et al., 2019); This variant is associated with the following publications: (PMID: 33471991, 18842000, 16825437, 30925164) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at