rs587780022
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_000465.4(BARD1):c.1718T>C(p.Ile573Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000254 in 1,613,920 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I573M) 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.1718T>C | p.Ile573Thr | missense_variant | 8/11 | ENST00000260947.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BARD1 | ENST00000260947.9 | c.1718T>C | p.Ile573Thr | missense_variant | 8/11 | 1 | NM_000465.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152180Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251320Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135828
GnomAD4 exome AF: 0.0000267 AC: 39AN: 1461740Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21AN XY: 727176
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74344
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 26, 2023 | The p.I573T variant (also known as c.1718T>C), located in coding exon 8 of the BARD1 gene, results from a T to C substitution at nucleotide position 1718. The isoleucine at codon 573 is replaced by threonine, an amino acid with similar properties. This alteration has been detected in a cohorts of individuals who underwent multi-gene panel testing for hereditary cancer (Yadav S et al. Fam Cancer, 2017 07;16:319-328; Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535; Benito-Sánchez B et al. Sci Rep, 2022 May;12:8547) as well as an individual with neuroblastoma (Lasorsa VA et al. Oncotarget, 2016 Apr;7:21840-52). This variant has also been reported in large breast cancer cohorts but has also been identified in several healthy control individuals (Weber-Lassalle N et al. Breast Cancer Res, 2019 04;21:55; Adedokun B et al. Cancer Epidemiol Biomarkers Prev, 2020 02;29:359-367; Kadri MSN et al. Front Oncol, 2020 Jan;10:568786; Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295; Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Aug 11, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 06, 2023 | This missense variant replaces isoleucine with threonine at codon 573 of the BARD1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast and/or ovarian cancer (PMID: 33552952). In two case-control studies this variant has not shown an association with breast cancer (PMID: 31036035, 33471991). This variant has been identified in 7/282712 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 | - - |
Familial cancer of breast Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 03, 2023 | This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 26, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 573 of the BARD1 protein (p.Ile573Thr). This variant is present in population databases (rs587780022, gnomAD 0.005%). This missense change has been observed in individual(s) with neuroblastoma and/or personal or family history of breast and/or ovarian cancer (PMID: 27009842, 27878467, 31036035, 31871109, 32658311, 33552952, 35595798). ClinVar contains an entry for this variant (Variation ID: 127722). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 08, 2023 | - - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 11, 2023 | Variant summary: BARD1 c.1718T>C (p.Ile573Thr) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251686 control chromosomes (gnomAD and Akcay_2020). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1718T>C has been reported in the literature in individuals with a personal or family history of breast or ovarian cancer (e.g., Yadav_2016, Adedokun_2020, Kadri_2021, Weber-Lasalle_2019, Benito-Sanchez_2022) as well as an individual affected with neuroblastoma (e.g., Lasorsa_2016). These reports however, do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31871109, 32658311, 35595798, 33552952, 27009842, 31036035, 27878467). Nine submitters have reported this variant to ClinVar after 2014 with conflicting interpretations (VUS, n = 8; likely benign, n = 1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 16, 2022 | Observed in individuals with breast cancer, ovarian cancer, or neuroblastoma (Lasorsa et al., 2016; Weber-Lassalle et al., 2019; Kadri et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27878467, 33552952, 31036035, 31871109, 27009842, 17550235, 32658311, 31159747) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 20, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at