rs760275914
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Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong
The NM_007294.4(BRCA1):c.4484+15T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000075 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 intron
NM_007294.4 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.504
Genes affected
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -12 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.84).
BP6
?
Variant 17-43076473-A-G is Benign according to our data. Variant chr17-43076473-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 415562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.4484+15T>C | intron_variant | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.4484+15T>C | intron_variant | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152156Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.00000797 AC: 2AN: 251092Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135744
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GnomAD4 exome AF: 0.00000753 AC: 11AN: 1460950Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 6AN XY: 726810
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ClinVar
Significance: Likely benign
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Malignant tumor of breast Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA1 c.4484+15T>C variant was not identified in the literature, nor was it identified in dbSNP, the 1000 Genomes Project, the NHLBI Exome Sequencing Project, GeneInsight COGR, COSMIC, MutDB, BRCA Share, BIC, ARUP Laboratories BRCA Mutations Database, the Fanconi Anemia Mutation Database (LOVD) or LOVD-IARC. This variant was identified in ClinVar(classified as likely benign by Invitae), Clinvitae (1X), and in the genome Aggregation Database (beta, October 19th 2016) in 2 of 252014 chromosomes (freq. 0.00001) and in the Exome Aggregation Consortium database (August 8th 2016) in 1 of 121336 chromosomes (freq. 0.00001) in the following populations: European in 1 of 66692 chromosomes (freq. 0.00001), but was not seen in African, Asian, Finnish, Latino and Other populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. This variant is classified as a variant of uncertain significance. - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 05, 2016 | - - |
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 28, 2023 | - - |
Computational scores
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BayesDel_noAF
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DANN
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at