rs80358163
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3PM2PP3PP5_Very_Strong
The NM_007294.4(BRCA1):c.213-12A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000296403: The inclusion of this intronic sequence alters the translation reading frame of the BRCA1 mRNA and is predicted to cause the synthesis of a truncated BRCA1 protein (PMID:23164213 (2012), 21735045 (2012), and 9805131 (1998))." and additional evidence is available in ClinVar. The gene BRCA1 is included in the ClinGen Criteria Specification Registry.
Frequency
Genomes: not found (cov: 32)
Consequence
BRCA1
NM_007294.4 intron
NM_007294.4 intron
Scores
2
Splicing: ADA: 0.9981
2
Clinical Significance
Conservation
PhyloP100: 0.312
Publications
26 publications found
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]
BRCA1 Gene-Disease associations (from GenCC):
- BRCA1-related cancer predispositionInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- breast-ovarian cancer, familial, susceptibility to, 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
- Fanconi anemia, complementation group SInheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
- pancreatic cancer, susceptibility to, 4Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- hereditary breast ovarian cancer syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Fanconi anemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Specifications for BRCA1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.
Classification was made for transcript
Our verdict: Pathogenic. The variant received 15 ACMG points.
PS3
PS3 evidence extracted from ClinVar submissions: SCV000296403: The inclusion of this intronic sequence alters the translation reading frame of the BRCA1 mRNA and is predicted to cause the synthesis of a truncated BRCA1 protein (PMID: 23164213 (2012), 21735045 (2012), and 9805131 (1998)).; SCV001548920: RT-PCR analysis on whole blood lymphocyte showed an 11 nucleotide insert at the intron 4/exon 6 boundary leading to a frameshift and truncated protein (Hoffman_1998_ 9805131).; SCV000683015: An RNA study has shown that this variant causes new splice acceptor that inserts 11 bp at the beginning of exon 6, resulting in frameshift and premature truncation within exon 6 (PMID: 9805131).; SCV000075739: Studies have shown that this variant results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 9805131; internal data).; SCV000271314: "In vitro functional studies provide evidence that the c.213-12A>G variant introduces a cryptic splice site, causing an additional 11 nucleotides to be retained and leading to a frameshift, which alters the protein's amino acid sequence beginning at position 71 and leads to a premature termination codon 21 amino acids downstream." PMID:9827874; SCV000698920: The variant was reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Hoffmann_1998). At least one publication reports experimental evidence that this variant affects mRNA splicing by incorporation of 11 bases of intron 5 leading to a frameshift in the codon sequence (Hoffman_1998).; SCV000806910: "This variant has been shown by RT-PCR to alter normal splicing of intron 5 (Hoffman et al., 1998. PubMed ID: 9805131; Menéndez et al., 2012. PubMed ID: 21735045)."
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 17-43104968-T-C is Pathogenic according to our data. Variant chr17-43104968-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 37450.Status of the report is reviewed_by_expert_panel, 3 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_007294.4. You can select a different transcript below to see updated ACMG assignments.
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | TSL:1 MANE Select | c.213-12A>G | intron | N/A | ENSP00000350283.3 | P38398-1 | |||
| BRCA1 | TSL:1 | c.213-12A>G | intron | N/A | ENSP00000418960.2 | P38398-7 | |||
| BRCA1 | TSL:1 | c.213-12A>G | intron | N/A | ENSP00000419274.2 | P38398-1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome
GnomAD4 genome
Cov.:
32
Alfa
AF:
Hom.:
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:reviewed by expert panel
Pathogenic
VUS
Benign
Condition
11
-
-
Breast-ovarian cancer, familial, susceptibility to, 1 (11)
10
-
-
not provided (10)
4
-
-
Hereditary breast ovarian cancer syndrome (4)
2
-
-
Hereditary cancer-predisposing syndrome (2)
1
-
-
BRCA1-related disorder (1)
1
-
-
Breast and/or ovarian cancer (1)
1
-
-
Familial cancer of breast (1)
1
-
-
Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S (1)
1
-
-
not specified (1)
1
-
-
Ovarian neoplasm (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
DANN
Benign
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
Splicevardb
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -1
DS_AL_spliceai
Position offset: -12
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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