17-43115730-A-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_007294.4(BRCA1):c.130T>A(p.Cys44Ser) 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. C44F) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
BRCA1
NM_007294.4 missense
NM_007294.4 missense
Scores
11
5
3
Clinical Significance
Conservation
PhyloP100: 4.03
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 18 ACMG points.
PM1
In a zinc_finger_region RING-type (size 41) in uniprot entity BRCA1_HUMAN there are 65 pathogenic changes around while only 6 benign (92%) 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 chr17-43115729-C-A is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.992
PP5
Variant 17-43115730-A-T is Pathogenic according to our data. Variant chr17-43115730-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 54191.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43115730-A-T is described in Lovd as [Pathogenic]. Variant chr17-43115730-A-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:15Uncertain:1Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:7Uncertain:1Other:1
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | Dec 23, 2003 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 24, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
| 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 | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | May 27, 2024 | PP3; PS3; PP1_Strong; PM2_Supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 13, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Medical Genetics, Oslo University Hospital | Jul 22, 2015 | - - |
| not provided, no classification provided | in vitro | Brotman Baty Institute, University of Washington | - | - - |
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 17, 2024 | The BRCA1 c.130T>A (p.Cys44Ser) variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMIDs: 33471991 (2021), 28888541 (2017), 19543972 (2010), 20104584 (2010), 20437199 (2010), 18182601 (2008)), and observed in screening studies of individuals with BRCA1 and BRCA2 pathogenic variants (PMIDs: 29339979 (2018), 29446198 (2018)). Functional studies indicate this variant has deleterious effects on BRCA1 protein function and DNA damage repair-associated cell survival (PMIDs: 30209399 (2018), 25823446 (2015)). 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 damaging. Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | May 27, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 10, 2019 | Published functional studies demonstrate a damaging effect: classified as non-functional based on a saturation genome editing assay assessing ability to support growth, and demonstrated defective homology-directed repair activity and BARD1 binding (Starita 2015, Findlay 2018, Caleca 2019); Multi-factorial studies suggest this variant is associated with breast and ovarian cancer (Lindor 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; No data available from control populations to assess the frequency of this variant; Observed in women with a history of breast and/or ovarian cancer and has been suggested to be a recurrent variant in the Greenlandic population (Borg 2010, Hansen 2010, Sweet 2010, Karami 2013); This variant is associated with the following publications: (PMID: 26295337, 21990134, 18182601, 19543972, 24489791, 20104584, 21520273, 20437199, 24312913, 25525159, 25823446, 30209399, 26833046, 21990165, 29339979, 29446198, 18465347, 30678073, 25348012, 30696104, 33087888) - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 15, 2024 | The p.C44S pathogenic mutation (also known as c.130T>A), located in coding exon 2 of the BRCA1 gene, results from a T to A substitution at nucleotide position 130. The cysteine at codon 44 is replaced by serine, an amino acid with dissimilar properties. This alteration occurs in the functionally important RING finger domain (Abkevich V et al. J. Med. Genet. 2004 Jul;41:492-507). This alteration has been reported in multiple individuals diagnosed with breast and/or ovarian cancer (Begg CB et al, JAMA 2008 Jan; 299(2):194-201; Hansen TV et al, Breast Cancer Res. Treat. 2010 Nov; 124(1):259-64; Sweet K et al, Breast Cancer Res. Treat. 2010 Feb; 119(3):737-43; Capanu M et al, Genet. Epidemiol. 2011 Jul; 35(5):389-97). One functional study found that this nucleotide substitution is non-functional in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 Oct;562:217-222). Two other alterations at the same codon, p.C44Y (c.131G>A) and p.C44F (c.131G>T), have been identified in multiple breast and/or ovarian cancer families (Alsop K et al. J. Clin. Oncol. 2012 Jul;30:2654-63; Jalkh N et al. Hered Cancer Clin Pract. 2012 Jun;10:7; George J et al. Clin. Cancer. Res. 2013 Jul;19:3474-84; Lolas Hamameh S et al. Int. J. Cancer. 2017 Aug;141:750-756). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 03, 2020 | This missense variant replaces cysteine with serine at codon 44 in the RING domain of the BRCA1 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). The variant protein has been shown to be functionally defective in a haploid cell proliferation assay (PMID 30209399). This variant has been reported in individuals affected with breast cancer (PMID: 19543972, 20104584) and ovarian cancer (PMID: 20437199). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different missense variants affecting the same codon, p.Cys44Tyr and p.Cys44Phe, are known to be pathogenic (Clinvar variation ID: 54199, 54200), indicating that cysteine at this position is important for BRCA1 function. Based on the available evidence, this variant is classified as Pathogenic. - |
Hereditary breast ovarian cancer syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 09, 2017 | Variant summary: The BRCA1 c.130T>A (p.Cys44Ser) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution at a highly conserved cysteine residue in the RING finger domain (InterPro). 5/5 in silico tools predict a damaging outcome for this variant. This variant is absent from the large control database ExAC and control cohorts reported in the literature (0/112062 control chromosomes). The variant has been identified in numerous HBOC patient. Several overlapping variants are present in HGMD (Cys44Arg, Cys44Gly, Cys44Phe, and Cys44Tyr), suggesting a mutational hotspot that is critical for protein function. In addition, this variant C44S has been functionally tested and shown to disrupt BARD1 binding, and impairs ubiquitin ligase activity and homolgy-directed repair (Starita_2015). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 17, 2023 | This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 44 of the BRCA1 protein (p.Cys44Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and ovarian cancer (PMID: 18182601, 18500671, 19543972, 20104584, 20437199). ClinVar contains an entry for this variant (Variation ID: 54191). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 12732733, 20029420, 25652403). This variant disrupts the p.Cys44 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16403807, 20103620, 21725363, 21922593, 21990134, 23161852, 27272900). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
.;T;.;.;.;D;.;T;T;.;T;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D;T;D;D;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;H;H;H;.;.;.;.;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N;D;N;.;N;N;N;D;D
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
0.98, 1.0, 1.0
.;D;.;.;D;.;D;.;.;.;.;.;.
Vest4
MutPred
Gain of disorder (P = 0.0935);Gain of disorder (P = 0.0935);Gain of disorder (P = 0.0935);Gain of disorder (P = 0.0935);Gain of disorder (P = 0.0935);Gain of disorder (P = 0.0935);Gain of disorder (P = 0.0935);Gain of disorder (P = 0.0935);Gain of disorder (P = 0.0935);Gain of disorder (P = 0.0935);Gain of disorder (P = 0.0935);Gain of disorder (P = 0.0935);Gain of disorder (P = 0.0935);
MVP
MPC
0.41
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