chr2-214730497-A-G
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2
The NM_000465.4(BARD1):c.1915T>C(p.Cys639Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000434 in 1,613,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. C639G) 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.1915T>C | p.Cys639Arg | missense_variant | 10/11 | ENST00000260947.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BARD1 | ENST00000260947.9 | c.1915T>C | p.Cys639Arg | missense_variant | 10/11 | 1 | NM_000465.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152170Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251322Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135826
GnomAD4 exome AF: 0.0000452 AC: 66AN: 1461640Hom.: 0 Cov.: 30 AF XY: 0.0000454 AC XY: 33AN XY: 727114
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74342
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 21, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 639 of the BARD1 protein (p.Cys639Arg). This variant is present in population databases (rs587781376, gnomAD 0.009%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 26534844, 30613976, 31036035, 31159747, 31512090, 35264596). ClinVar contains an entry for this variant (Variation ID: 140927). 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 disruptive. 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:3
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 10, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 15, 2016 | Variant summary: The c.1915T>C (p.Cys639Arg) in BARD1 gene is a missense change that involves a highly conserved nucleotide and 5/5 in silico tools predict deleterious outcome. The variant falls into the BRCT domain, and mutations in this domain have been shown to be associated with cancer. The variant is present in the control population dataset of ExAC at an overall frequency 0.000017 (2/121244 chrs tested). This frequency does not exceed the estimated maximum allele frequency for a pathogenic allele in this gene (0.0002). The variant was identified in at least 1 HBOC BRCA1&2-negative family, with no information on segregation and co-occurrence provided by the authors (Li, 2016). The variant of interest has been reported as VUS by reputable database/clinical laboratory. Additional clinical, segregation and population data needed to classify this variant with confidence. Taking together, the variant was classified as VUS. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 17, 2021 | Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history including breast and/ovarian cancer (Li 2016, Scarpitta 2019, Weber-Lassalle 2019); This variant is associated with the following publications: (PMID: 17550235, 31036035, 31512090, 26534844, 31159747, 27535533) - |
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 13, 2023 | The p.C639R variant (also known as c.1915T>C), located in coding exon 10 of the BARD1 gene, results from a T to C substitution at nucleotide position 1915. The cysteine at codon 639 is replaced by arginine, an amino acid with highly dissimilar properties. This variant has been identified in numerous disease cohorts as well as unaffected control groups across studies (Li J et al. J. Med. Genet., 2016 Jan;53:34-42; Scarpitta R et al. Breast Cancer Res Treat, 2019 Dec;178:557-564; Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535; Weber-Lassalle N et al. Breast Cancer Res, 2019 04;21:55; Dorling et al. N Engl J Med. 2021 02;384:428-439; Rizzolo P et al. Int J Cancer, 2019 Jul;145:390-400; Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 01, 2023 | This missense variant replaces cysteine with arginine at codon 639 of the BARD1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals with a personal or family history of breast and/or ovarian cancer (PMID: 26534844, 31036035, 31159747, 31512090, 36980780). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 6/60466 cases and 4/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID BARD1_000127). This variant has been identified in 7/251322 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 | GeneKor MSA | Aug 01, 2018 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Feb 06, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at