rs273902786
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_007294.4(BRCA1):c.754C>T(p.Arg252Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,459,730 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R252R) has been classified as Benign.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 missense
NM_007294.4 missense
Scores
3
7
9
Clinical Significance
Conservation
PhyloP100: 3.73
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 Likely_benign. Variant got -1 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.37503648).
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.754C>T | p.Arg252Cys | missense_variant | 10/23 | ENST00000357654.9 | NP_009225.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | ENST00000357654.9 | c.754C>T | p.Arg252Cys | missense_variant | 10/23 | 1 | NM_007294.4 | ENSP00000350283.3 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1459730Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 726160
GnomAD4 exome
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6
AN:
1459730
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Cov.:
33
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3
AN XY:
726160
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:7Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:3
| Uncertain significance, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Jul 20, 2010 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jan 22, 2016 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | Sep 18, 2010 | - - |
Hereditary cancer-predisposing syndrome Benign:3
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 30, 2019 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 19, 2017 | - - |
| Likely benign, criteria provided, single submitter | curation | University of Washington Department of Laboratory Medicine, University of Washington | Mar 23, 2023 | Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 14, 2021 | Variant summary: BRCA1 c.754C>T (p.Arg252Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249320 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.754C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer without strong evidence for causality (examples- Thirthagiri_2008, Bhaskaran_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Starita_2015). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=2, VUS, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Breast and/or ovarian cancer Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | - | - - |
not provided Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 25, 2023 | In the published literature, this variant has been reported in an individual affected with breast cancer (PMID: 32868316 (2020)) and in a family with a high risk of breast or ovarian cancer (PMID: 18627636 (2008)). One functional study observed the variant to have reduced E3 ligase activity compared to the wild type (PMID: 25823446 (2015)), however, further research is needed. This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Hereditary breast ovarian cancer syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 252 of the BRCA1 protein (p.Arg252Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 18627636, 30702160, 32868316). ClinVar contains an entry for this variant (Variation ID: 55688). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.;.;.;.;.;T;.;T;.;T;T;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
N;N;N;.;N;.;.;.;.;.;.;.;.;.
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;N;N;N;N;N;N;N;.;N;N;N
REVEL
Uncertain
Sift
Uncertain
D;D;D;D;D;D;D;D;D;D;.;D;D;D
Sift4G
Uncertain
T;D;T;T;T;.;.;T;.;D;.;D;.;D
Polyphen
P;.;.;.;P;.;P;.;.;P;.;.;.;.
Vest4
MutPred
Gain of methylation at K251 (P = 0.0202);Gain of methylation at K251 (P = 0.0202);Gain of methylation at K251 (P = 0.0202);.;Gain of methylation at K251 (P = 0.0202);.;.;.;.;Gain of methylation at K251 (P = 0.0202);.;Gain of methylation at K251 (P = 0.0202);.;Gain of methylation at K251 (P = 0.0202);
MVP
MPC
0.27
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
Find out detailed SpliceAI scores and Pangolin per-transcript scores at