17-43051071-A-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_007294.4(BRCA1):c.5324T>A(p.Met1775Lys) variant causes a missense change. 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 Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1775R) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 31)
Consequence
BRCA1
NM_007294.4 missense
NM_007294.4 missense
Scores
10
6
1
Clinical Significance
Conservation
PhyloP100: 5.03
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 16 ACMG points.
PM1
?
In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 9 benign, 17 uncertain in NM_007294.4
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr17-43051071-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 17694.Status of the report is reviewed_by_expert_panel, 3 stars.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.899
PP5
?
Variant 17-43051071-A-T is Pathogenic according to our data. Variant chr17-43051071-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 17695.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43051071-A-T is described in Lovd as [Pathogenic]. Variant chr17-43051071-A-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.5324T>A | p.Met1775Lys | missense_variant | 20/23 | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.5324T>A | p.Met1775Lys | missense_variant | 20/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:5Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2008 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Jun 21, 2010 | - - |
not provided, no classification provided | in vitro | Brotman Baty Institute, University of Washington | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Jun 02, 2021 | The BRCA1 c.5324T>A variant is classified as Pathogenic (PS3, PM2, PM5, PP3, PP5) - |
Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Aug 10, 2015 | IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 1 - |
Pathogenic, criteria provided, single submitter | clinical testing | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 15, 2020 | This missense variant replaces methionine with lysine at codon 1775 in the BRCT2 domain 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 shown that the mutant protein is highly defective for specific phosphopeptide recognition and transcriptional activity (PMID: 18285836, 20516115). This variant has also been reported to cause loss of BRCA1 function in a haploid cell proliferation assay (PMID: 30209399). This variant has been observed in two individuals affected with familial breast cancer (PMID: 18285836) and reported to be disease-causing based on multifactorial likelihood analyses (PMID: 18285836, 21990134). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same codon, p.Met1775Arg, is a well documented pathogenic mutation (Clinvar variation ID: 17694), indicating that methionine at this position is important for BRCA1 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 24, 2020 | The p.M1775K variant (also known as c.5324T>A), located in coding exon 19 of the BRCA1 gene, results from a T to A substitution at nucleotide position 5324. The methionine at codon 1775 is replaced by lysine, an amino acid with similar properties. This alteration, as well as a known pathogenic close match alteration BRCA2 p.M1775R, were non-functional in many different assays including a colony size assay, a haploid cell survival assay, multiple transcription activation assays, and multiple protein binding and specificity assays (Thouvenot P et al. PLoS Genet. 2016 06;12:e1006096; Findlay GM et al. Nature. 2018 10;562:217-222; Lee MS et al. Cancer Res. 2010 Jun;70:4880-90; Tischkowitz M et al. Eur. J. Hum. Genet. 2008 Jul;16:820-32; Drikos I et al. Proteins. 2009 Nov;77:464-76). This alteration was identified in two families in the literature and segregated with disease in both. In one family, this variant was found in cis with BRCA2 p.D1778N, a likely pathogenic splicing alteration (Tischkowitz M et al. Eur. J. Hum. Genet. 2008 Jul;16:820-32). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic - |
Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, 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
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
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
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;N;.;D;.;.;N;D
REVEL
Pathogenic
Sift
Uncertain
D;D;.;D;.;.;D;D
Sift4G
Pathogenic
D;D;D;D;D;D;D;D
Polyphen
0.99, 1.0
.;D;.;.;.;D;.;.
Vest4
MVP
MPC
0.56
ClinPred
D
GERP RS
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