rs745929983
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6BS2_Supporting
The NM_000465.4(BARD1):c.365-7C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000413 in 1,596,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000465.4 splice_region, splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BARD1 | NM_000465.4 | c.365-7C>T | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000260947.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BARD1 | ENST00000260947.9 | c.365-7C>T | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000465.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 151866Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000377 AC: 9AN: 238706Hom.: 0 AF XY: 0.0000617 AC XY: 8AN XY: 129742
GnomAD4 exome AF: 0.0000422 AC: 61AN: 1445096Hom.: 0 Cov.: 31 AF XY: 0.0000347 AC XY: 25AN XY: 719456
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 151866Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74184
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 15, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 24, 2022 | Variant summary: BARD1 c.365-7C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.8e-05 in 238706 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.365-7C>T has been reported in the literature in individuals affected with Hereditary Breast Cancer without evidence for causality (example: De Brakeleer_2010) . This report does 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 11, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Familial cancer of breast Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 04, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 04, 2016 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 16, 2023 | - - |
Malignant tumor of breast Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BARD1 c.365-7C>T variant was identified in 1 of 392 proband chromosomes (frequency: 0.003) from individuals or families with breast cancer (De Brakeleer 2010). The variant was identified in dbSNP (rs745929983) as “with likely benign allele” and ClinVar (classified as likely benign by Invitae, Color, GeneDx and Quest Diagnostics). The variant was identified in control databases in 10 of 269,488 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6824 chromosomes (freq: 0.0001), Latino in 2 of 33,564 chromosomes (freq: 0.00006), European in 6 of 123,604 chromosomes (freq: 0.00005), and African in 1 of 23,536 chromosomes (freq: 0.00004), while it was not observed in the Ashkenazi Jewish, East Asian, Finnish or South Asian populations. The variant occurs at a non-highly conserved nucleotide outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at