rs28897698
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3PP5
The ENST00000357654.9(BRCA1):c.5425G>T(p.Val1809Phe) variant causes a missense 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1809A) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
BRCA1
ENST00000357654.9 missense
ENST00000357654.9 missense
Scores
6
6
4
Clinical Significance
Conservation
PhyloP100: 1.17
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 17 uncertain in ENST00000357654.9
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-43047684-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 825725.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.835
PP5
Variant 17-43047685-C-A is Pathogenic according to our data. Variant chr17-43047685-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 55573.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=2}. Variant chr17-43047685-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.5425G>T | p.Val1809Phe | missense_variant | 22/23 | ENST00000357654.9 | NP_009225.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | ENST00000357654.9 | c.5425G>T | p.Val1809Phe | missense_variant | 22/23 | 1 | NM_007294.4 | ENSP00000350283 | P4 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:2
| Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 28, 2021 | Published functional studies demonstrate a damaging effect: decreased transcriptional activity, peptide binding activity and specificity (Williams 2004, Phelan 2005, Fernandes 2019, Drikos 2021); Observed in individuals with breast and ovarian cancer, segregating with disease in one family (Phelan 2005, Thomassen 2008, Fostira 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Not observed in large population cohorts (Lek et al., 2016); Also known as 5544G>T; This variant is associated with the following publications: (PMID: 16528612, 31131967, 15689452, 17305420, 19452558, 21447777, 15172985, 20516115, 14534301, 15133503, 18465347, 15385441, 20167696, 17719744, 28781887, 30765603, 31300551, 32123317, 32546644, 34083286) - |
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1Uncertain:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Oct 02, 2023 | This missense variant replaces valine with phenylalanine at codon 1809 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant impacts BRCA1 in homology-directed repair, transcription activation and cisplatin and olaparib sensitivity assays and may compromise protein stability, protein localization, and protein-protein interaction (PMID: 14534301, 15133503, 15689452, 16528612, 19452558, 20516115, 28781887, 32546644, 34083286). This variant has been observed in multiple individuals affected with breast cancer from at least three unrelated families (PMID: 15689452, 18465347, 31300551, 33471991; Leiden Open Variation Database DB-ID BRCA1_000474), including an individual affected with breast and endometrial cancer (PMID: 31300551) and the co-segregation with four affected members of a hereditary breast cancer family (PMID: 15689452). 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 Likely Pathogenic. - |
| Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 06, 2023 | The p.V1809F variant (also known as c.5425G>T), located in coding exon 21 of the BRCA1 gene, results from a G to T substitution at nucleotide position 5425. The valine at codon 1809 is replaced by phenylalanine, an amino acid with highly similar properties. This variant has been identified in breast cancer cohorts and has been shown to segregate with disease in one family (Phelan CM et al. J Med Genet, 2005 Feb;42:138-46; Thomassen M et al. Acta Oncol, 2008;47:772-7; Fostira F et al. J Med Genet 2020 Jan;57(1):53-61). Protein functional studies have demonstrated this variant to have a deleterious impact on function (Bouwman P et al. Clin Cancer Res, 2020 Sep;26:4559-4568; Woods NT et al. NPJ Genom Med, 2016 Mar;1:16001; Fernandes VC et al. J Biol Chem, 2019 Apr;294:5980-5992; Lee MS et al. Cancer Res, 2010 Jun;70:4880-90; Drikos I et al. Anticancer Res, 2021 Jun;41:2953-2962). This alteration was inconclusive in a multifactorial model of variant interpretation that incorporates co-segregation, family history, co-occurrence, tumor pathology and case-control data (Parsons MT et al. Hum Mutat 2019 Sep;40(9):1557-1578). Of note, this alteration is also referred to as c.5544G>T in published literature. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 31, 2023 | This missense variant replaces valine with phenylalanine at codon 1809 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant impacts BRCA1 in homology-directed repair, transcription activation and cisplatin and olaparib sensitivity assays and may compromise protein stability, protein localization, and protein-protein interaction (PMID: 14534301, 15133503, 15689452, 16528612, 19452558, 20516115, 28781887, 32546644, 34083286). This variant has been observed in multiple individuals affected with breast cancer from at least three unrelated families (PMID: 15689452, 18465347, 31300551, 33471991; Leiden Open Variation Database DB-ID BRCA1_000474), including an individual affected with breast and endometrial cancer (PMID: 31300551) and the co-segregation with four affected members of a hereditary breast cancer family (PMID: 15689452). 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 Likely Pathogenic. - |
Hereditary breast ovarian cancer syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 05, 2024 | This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1809 of the BRCA1 protein (p.Val1809Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a personal and/or family history of breast, ovarian and/or endometrial cancer (PMID: 15689452, 18465347, 31300551). It has also been observed to segregate with disease in related individuals. This variant is also known as 5544G>T. ClinVar contains an entry for this variant (Variation ID: 55573). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BRCA1 protein function. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 15689452, 19452558, 20516115, 28781887, 32546644, 34083286). 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
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;N;N;N;N;N;N;N;N;N;N;N;N;N
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Vest4
MutPred
Gain of sheet (P = 0.0266);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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