chr17-43124094-C-T
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.3G>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
BRCA1
NM_007294.4 start_lost
NM_007294.4 start_lost
Scores
6
5
4
Clinical Significance
Conservation
PhyloP100: 3.43
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 Pathogenic. Variant got 20 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PS1
?
Another start lost variant in NM_007294.4 (BRCA1) was described as [Pathogenic] in ClinVar as 55072
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 17-43124094-C-T is Pathogenic according to our data. Variant chr17-43124094-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 431194.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43124094-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.3G>A | p.Met1? | start_lost | 2/23 | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.3G>A | p.Met1? | start_lost | 2/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4Uncertain:1Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1Other:1
not provided, no classification provided | in vitro | Brotman Baty Institute, University of Washington | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
not provided Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA1 p.Met1? variant was identified in 3 of 59400 proband chromosomes (frequency: 0.00005) from families in a worldwide study by Rebbeck (2018). The variant was also identified in LOVD 3.0 (1x as pathogenic). Please note another variants, c.3G>T and c.3G>C at the same position with different nucleotide change and same amino acid change, p.Met1? were found in ClinVar Database and were classified as pathogenic by multiple submitters. The c.3G>A variant occurs in the first base of the translation initiation site (the methionine amino acid start site), increasing the likelihood this variant may disrupt translation or lead to an abnormal protein product. The variant was not identified in dbSNP, ClinVar, or UMD-LSDB. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 29, 2021 | This variant disrupts the translation initiation codon of the BRCA1 protein and is expected to result in an absent or non-functional protein product. A functional study has reported that this variant impacts BRCA1 function in a haploid human cell proliferation assay (PMID: 30209399). This variant has been observed in at least two individuals affected with breast cancer (PMID: 9145677; Color internal data). Different variants that also disrupted the translation initiation codon, p.Met1, have also been reported in at least eight individuals affected with breast, ovarian and fallopian tube cancer (PMID: 11595708, 12827452, 16912212, 22006311, 24504028, 24884479, 25480878, 32008151, 33471991; Leiden Open Variation Database DB-ID BRCA1_002590). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 21, 2022 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Studies have shown that disruption of the initiator codon alters BRCA1 gene expression (PMID: 21922593). ClinVar contains an entry for this variant (Variation ID: 431194). A different variant (c.1A>G, c.2T>G, c.2T>C, and c.3G>T) giving rise to the same protein effect has been determined to be pathogenic (PMID: 10923033, 11595708, 11802209, 12827452, 21120943, 22006311, 24504028). This suggests that this variant is also likely to be causative of disease. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the BRCA1 mRNA. The next in-frame methionine is located at codon 18. - |
not specified Uncertain:1
Uncertain significance, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D;D;D;D;D
PROVEAN
Benign
N;N;N;N;N;N;N;.;N;N;N;D;N;.
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;D;D;.;D;D;D;D;D;.
Sift4G
Benign
T;D;D;T;T;.;D;.;D;.;D;.;.;.
Polyphen
0.92, 0.66, 0.99
.;P;.;.;P;.;D;.;.;.;.;.;.;.
Vest4
MutPred
Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);Gain of catalytic residue at M1 (P = 0.0314);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: 21
Find out detailed SpliceAI scores and Pangolin per-transcript scores at