17-43093742-C-T
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong
The NM_007294.4(BRCA1):c.1789G>A(p.Glu597Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,613,814 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E597D) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00017 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 missense
NM_007294.4 missense
Scores
1
12
6
Clinical Significance
Conservation
PhyloP100: 1.24
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 -8 ACMG points.
BP6
Variant 17-43093742-C-T is Benign according to our data. Variant chr17-43093742-C-T is described in ClinVar as [Benign]. Clinvar id is 41806.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43093742-C-T is described in Lovd as [Benign].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.1789G>A | p.Glu597Lys | missense_variant | 10/23 | ENST00000357654.9 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | ENST00000357654.9 | c.1789G>A | p.Glu597Lys | missense_variant | 10/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes 0.000178 AC: 27AN: 152108Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000797 AC: 20AN: 251080Hom.: 0 AF XY: 0.0000737 AC XY: 10AN XY: 135758
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GnomAD4 exome AF: 0.000166 AC: 242AN: 1461706Hom.: 0 Cov.: 34 AF XY: 0.000144 AC XY: 105AN XY: 727148
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GnomAD4 genome 0.000178 AC: 27AN: 152108Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15AN XY: 74296
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ClinVar
Significance: Benign
Submissions summary: Uncertain:4Benign:13
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Benign:3
| 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 | Sharing Clinical Reports Project (SCRP) | Nov 20, 2008 | - - |
| 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 = 0.0000000000692 - |
| Likely benign, no assertion criteria provided | clinical testing | Pathway Genomics | Nov 06, 2014 | - - |
not specified Benign:3
| Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 20, 2018 | - - |
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 24, 2020 | Variant summary: BRCA1 c.1789G>A (p.Glu597Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.3e-05 in 252224 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (8.3e-05 vs 0.001), allowing no conclusion about variant significance. c.1789G>A has been reported in the literature in individuals affected with breast and/or ovarian cancer (example, Judkins_2005, Lee_2008, Easton_2007, Borg_2010, Capanu_2011, Spearman_2008, Alsop_2012, Lu_2012, Maxwell_2014, Zhang_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multifactorial probability models predict a neutral outcome (Lindor_2012). At-least one co-occurrence with another pathogenic variant has been reported in the BIC database (BRCA2 c.6373_6374insA, p.Thr2125?fs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 18, 2018 | 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. - |
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 | Jul 17, 2015 | - - |
| Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jun 24, 2021 | - - |
not provided Uncertain:1Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 01, 2023 | - - |
| Uncertain significance, no assertion criteria provided | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jul 13, 2012 | - - |
Hereditary breast ovarian cancer syndrome Uncertain:1Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Jun 15, 2023 | - - |
| Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Malignant tumor of breast Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA1 p.Glu597Lys variant was identified in 7 of 7414 proband chromosomes (frequency: 0.0009) from individuals or families with breast cancer (Goidescu 2017, Momozawa 2018, Johnston 2012, Borg 2010, Lee 2008) and was identified in 6 of 48666 chromosomes (frequency: 0) from healthy individuals. In silico prediction models looking at causality likelihood ratios and posterior probability suggest the variant is neutral/not pathogenic (Easton 2007, Lindor 2012). The variant was identified in dbSNP (ID: rs55650082) “With Pathogenic, other allele”, ClinVar (classified benign, reviewed by an expert panel (2015); submitters: benign by ENIGMA, Ambry Genetics; likely benign by Color, Integrated Genetics/Laboratory Corporation of America, Invitae, GeneDx, SCRP and Pathway Genomics; uncertain significance by BIC and Biesecker Lab/Human Development Section (NIH)), LOVD 3.0 (1x), BIC Database (16X with unknown clinical importance, pending classification) and ARUP Laboratories (classified as 1 - not pathogenic or of no clinical significance). The variant was not identified in UMD-LSDB database. The variant was also identified in control databases in 22 of 276862 chromosomes at a frequency of 0.00008 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017), observed in the following populations: African in 3 of 23996 chromosomes (freq: 0.0001), European Non-Finnish in 18 of 126494 chromosomes (freq: 0.0001), and South Asian in 1 of 30778 chromosomes (freq: 0.00003) while not observed in the Other, Latino, Ashkenazi Jewish, East Asian and European Finnish populations. The p.Glu597 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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. This variant is classified as a variant of uncertain significance. - |
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 | Mar 06, 2020 | - - |
BRCA1-related disorder Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 01, 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
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.;.;T;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D;D;.;D;D
REVEL
Uncertain
Sift
Benign
T;T;T;T;.;T;T
Sift4G
Benign
T;T;T;T;.;T;.
Polyphen
D;.;.;D;.;.;.
Vest4
MVP
MPC
0.48
ClinPred
T
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at