chr17-43093054-G-T
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4BP6_Very_Strong
The NM_007294.4(BRCA1):c.2477C>A(p.Thr826Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000341 in 1,613,812 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).
Frequency
Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00036 ( 1 hom. )
Consequence
BRCA1
NM_007294.4 missense
NM_007294.4 missense
Scores
3
7
9
Clinical Significance
Conservation
PhyloP100: 0.182
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 Benign. Variant got -9 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.27411184).
BP6
Variant 17-43093054-G-T is Benign according to our data. Variant chr17-43093054-G-T is described in ClinVar as [Benign]. Clinvar id is 37473.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43093054-G-T is described in Lovd as [Benign]. Variant chr17-43093054-G-T is described in Lovd as [Pathogenic]. Variant chr17-43093054-G-T is described in Lovd as [Likely_benign].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.2477C>A | p.Thr826Lys | 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.2477C>A | p.Thr826Lys | missense_variant | 10/23 | 1 | NM_007294.4 | ENSP00000350283.3 |
Frequencies
GnomAD3 genomes 0.000204 AC: 31AN: 152130Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000179 AC: 45AN: 250902Hom.: 0 AF XY: 0.000162 AC XY: 22AN XY: 135618
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GnomAD4 exome AF: 0.000355 AC: 519AN: 1461564Hom.: 1 Cov.: 40 AF XY: 0.000329 AC XY: 239AN XY: 727110
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GnomAD4 genome 0.000204 AC: 31AN: 152248Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74434
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ClinVar
Significance: Benign
Submissions summary: Uncertain:3Benign:27
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2Benign:6
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
| Benign, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
| Benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | May 01, 2012 | - - |
| Likely benign, criteria provided, single submitter | literature only | Counsyl | Jun 12, 2014 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
| Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA1 p.Thr826Lys variant was identified in 12 of 6080 proband chromosomes (frequency: 0.002) from individuals or families with breast or ovarian cancer and was not identified in 372 control chromosomes from healthy individuals (Simard 2007, Capanu 2011, Tonin 1998, Palomba 2009, Klemp 2000, Dean 2015). The variant was identified in dbSNP (rs28897683) as “with other allele”, ClinVar (classified as benign by ENIGMA expert panel in 2015, Invitae, Ambry Genetics, Gene Dx and 6 other submitters; as likely benign by Counsyl, Color and 2 other submitters; and as uncertain significance by BIC and 3 other submitters), LOVD 3.0 (observed 17x) and UMD-LSDB (observed 33x). The variant was identified in control databases in 52 of 276616 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 4 of 24,028 chromosomes (freq: 0.0002), Latino in 8 of 34,412 chromosomes (freq: 0.0002) and European in 40 of 126,296 chromosomes (freq: 0.0003), while the variant was not observed in the Other, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The variant was observed in the UMD-LSDB database in 3 cases with co-occurring pathogenic variants: BRCA1 c.3669del (p.Cys1225Alafs*10), BRCA1 c.4251_4252del (p.Leu1418Argfs*9), and BRCA2 c.6359C>G (p.Ser2120*). In a complementation assay in BRCA1-deficient mouse embryonic stem cells, the variant was demonstrated to have no observed effect on cell proliferation and sensitivity to cisplatin, indicating the variant protein activity was sufficient to complement the BRCA1-null cells (Bouwman 2013). The p.Thr826 residue is conserved in mammals but not in more distantly related organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
| Benign, 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 1 based on posterior probability = 0.00000000203 - |
| Benign, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | May 03, 2020 | - - |
not specified Benign:8
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 17, 2017 | 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. - |
| Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 31, 2022 | The p.Thr826Lys variant in BRCA1 is classified as likely benign because it has been identified in 0.03% (40/128816) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as Benign on August 10, 2015 by the ClinGen-approved ENIGMA expert panel (Variation ID 37473). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. ACMG/AMP Criteria applied: BS1, BP4. - |
| Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 07, 2014 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
| Likely benign, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 30, 2022 | - - |
| Benign, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
| Benign, criteria provided, single submitter | clinical testing | Department of Pathology and Molecular Medicine, Queen's University | Apr 20, 2017 | - - |
Hereditary breast ovarian cancer syndrome Benign:4
| Likely benign, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Apr 25, 2016 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Nov 16, 2021 | - - |
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Aug 26, 2021 | The BRCA1 c.2477C>A (p.Thr826Lys) missense change has a maximum subpopulation frequency of 0.031% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/17-41245071-G-T). In silico tools are not in agreement about the effect of this variant on protein function, however in vitro functional studies have shown that this variant results in an activity comparable to the wild type in cell proliferation and cisplatin sensitivity assays (BS3; PMID: 23867111). This variant has been reported in four women older than 70 years of age who have never had cancer (BS2_supporting; https://whi.color.com/variant/17-41245071-G-T). In addition, this variant has been reported to co-occur with pathogenic variants in BRCA1 and BRCA2 (BP2; UMD database). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS3, BS2_supporting, BP2. - |
not provided Benign:3
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | BRCA1: BS3:Supporting, BS2 - |
| Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 14, 2023 | - - |
Hereditary cancer-predisposing syndrome Benign:3
| Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 18, 2014 | This alteration is classified as 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 | Feb 11, 2015 | - - |
| Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 30, 2020 | - - |
Breast neoplasm Uncertain:1
| Uncertain significance, criteria provided, single submitter | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | Low GERP score may suggest that this variant may belong in a lower pathogenicity class - |
Breast and/or ovarian cancer Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jul 14, 2021 | - - |
BRCA1-related cancer predisposition Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 23, 2024 | - - |
BRCA1-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 05, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Benign
DEOGEN2
Uncertain
D;.;.;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
M;M;.;.;.
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;D;D;D;.
REVEL
Uncertain
Sift
Uncertain
D;D;D;D;.
Sift4G
Benign
T;T;T;T;.
Polyphen
P;.;.;D;.
Vest4
MVP
MPC
0.21
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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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