rs80357002
Positions:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_007294.4(BRCA1):c.4765C>T(p.Arg1589Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,884 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1589P) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000013 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 missense
NM_007294.4 missense
Scores
1
6
12
Clinical Significance
Conservation
PhyloP100: 0.345
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 -3 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.23940855).
BP6
Variant 17-43071149-G-A is Benign according to our data. Variant chr17-43071149-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 55283.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=3}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.4765C>T | p.Arg1589Cys | missense_variant | 15/23 | ENST00000357654.9 | NP_009225.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | ENST00000357654.9 | c.4765C>T | p.Arg1589Cys | missense_variant | 15/23 | 1 | NM_007294.4 | ENSP00000350283.3 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251386Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135858
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GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461884Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7AN XY: 727242
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32
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:9
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:2Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 19, 2016 | 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 28, 2020 | DNA sequence analysis of the BRCA1 gene demonstrated a sequence change, c.4765C>T, in exon 15 that results in an amino acid change, p.Arg1589Cys. This sequence change has been described in the gnomAD database in three individuals (dbSNP rs80357002). The p.Arg1589Cys change has been described in one individual from a hereditary breast and ovarian cancer family (PMID: 16267036). The p.Arg1589Cys change affects a poorly conserved amino acid residue located in a domain of the BRCA1 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg1589Cys substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg1589Cys change remains unknown at this time. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 06, 2024 | Variant summary: BRCA1 c.4765C>T (p.Arg1589Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251386 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant has been reported in HBOC families, however with limited information (i.e. no data about co-occurrence and cosegregation provided) (example, Judkins_2005, Lincoln_2015, Kim_2020). However, a reputable database (BIC) cites the variant to co-occur with a pathogenic BRCA2 variant (c.1929delG), suggesting that it was not a primary cause of disease in the patient. A large case-control study evaluating breast cancer genetic risk also reported this variant was absent in the case cohorts (Dorling_2021, 1/53461 controls). In addition, this variant had similar transcription activation activity in comparison to wildtype (Woods_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. The following publications have been ascertained in the context of this evaluation (PMID: 33471991, 16267036, 31907386, 26207792, 15385441, 28781887). ClinVar contains an entry for this variant (Variation ID: 55283). Based on the evidence outlined above, the variant was classified as uncertain significance-possibly benign. - |
| Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2Benign:2
| Benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Aug 10, 2012 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | Feb 20, 2004 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Endocrinology Laboratory, Christian Medical College | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Oct 23, 2023 | - - |
Hereditary cancer-predisposing syndrome Benign:4
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 26, 2018 | 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 | Nov 21, 2016 | - - |
| Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 28, 2021 | - - |
| Likely benign, no assertion criteria provided | clinical testing | True Health Diagnostics | May 30, 2018 | - - |
Hereditary breast ovarian cancer syndrome Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
.;T;.;.;T;.;.;.;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
D;D;D;T;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;N;.;.;.;.;.;.;.;.
PrimateAI
Benign
T
PROVEAN
Benign
N;N;.;N;.;N;N;N;N;N
REVEL
Uncertain
Sift
Uncertain
D;D;.;D;.;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;T;D;D;.;.;D
Polyphen
0.096, 0.27
.;B;.;.;.;.;.;.;B;.
Vest4
MVP
MPC
0.20
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at