17-43092947-T-C
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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.2584A>G(p.Lys862Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,613,700 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000042 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 missense
NM_007294.4 missense
Scores
2
12
5
Clinical Significance
Conservation
PhyloP100: 2.71
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 17-43092947-T-C is Benign according to our data. Variant chr17-43092947-T-C is described in ClinVar as [Benign]. Clinvar id is 37476.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43092947-T-C is described in Lovd as [Benign].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.2584A>G | p.Lys862Glu | 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.2584A>G | p.Lys862Glu | missense_variant | 10/23 | 1 | NM_007294.4 | ENSP00000350283.3 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152222Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251066Hom.: 0 AF XY: 0.0000590 AC XY: 8AN XY: 135700
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GnomAD4 exome AF: 0.0000417 AC: 61AN: 1461478Hom.: 0 Cov.: 42 AF XY: 0.0000399 AC XY: 29AN XY: 727028
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GnomAD4 genome 0.00000657 AC: 1AN: 152222Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74370
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ClinVar
Significance: Benign
Submissions summary: Uncertain:2Benign:16
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 | - - |
| Benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Feb 10, 2010 | - - |
| 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 = 0.00000991 - |
| Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
not provided Uncertain:1Benign:3
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 09, 2021 | The BRCA1 c.2584A>G; p.Lys862Glu variant (rs80356927) is reported in the literature in individuals affected with breast and/or ovarian cancer, although it was no demonstrated to be disease-causing (Peyrat 1998). This variant is reported as benign or likely benign by multiple laboratories in ClinVar (Variation ID: 37476), and it is found in the general population with an overall allele frequency of 0.01% (16/282472 alleles) in the Genome Aggregation Database. The lysine at codon 862 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.808). However, multifactorial likelihood analysis considering family history of disease, co-occurrence with pathogenic variants, and co-segregation with disease suggest this variant has very low odds of causing disease (Easton 2007, Lindor 2012). However, given the lack of clinical and functional data, the significance of the p.Lys862Glu variant is uncertain at this time. References: Easton DF et al. A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. Am J Hum Genet. 2007 Nov;81(5):873-83. PMID: 17924331. Lindor NM et al. A review of a multifactorial probability-based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS). Hum Mutat. 2012 Jan;33(1):8-21. PMID: 21990134 Peyrat JP et al. Germline BRCA1 mutations in patients from 84 families with breast and/or ovarian cancers in northern France. Eur J Cancer Prev. 1998 Feb;7 Suppl 1:S7-12. PMID: 10866029. - |
| Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 19, 2023 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 27, 2019 | This variant is associated with the following publications: (PMID: 21990134, 16518693, 22753008, 17924331, 26306726, 16267036, 23893897, 18273839, 25682074, 18951461, 18779604, 15385441, 25348012, 29453630) - |
not specified Benign:3
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 26, 2019 | Variant summary: BRCA1 c.2584A>G (p.Lys862Glu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251066 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (6e-05 vs 0.001), allowing no conclusion about variant significance. c.2584A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, however these reports do not provide evidence for pathogenicity (Judkins_2005, Wong-Brown_2015, Anczukow_2008, Kurian_2008, Minucci_2015, Peyrat_1998, Li_2018, Kraemer_2019). In addition, multifactorial probability models, performing systematic assessments of variants of unknown significance in the BRCA genes, which included analysis of co-occurrence in trans with known deleterious mutations, personal and family history of cancer, tumor pathology and co-segregation with disease in pedigrees, predicted this variant to be neutral (Easton 2007 and Lindor 2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other submitters, including one expert panel (ENIGMA), have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign while the expert panel has classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. - |
| Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 13, 2017 | - - |
| Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
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 | Nov 25, 2015 | - - |
| Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jun 22, 2021 | - - |
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 | Apr 09, 2021 | - - |
Malignant tumor of breast Benign:1
| Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA1 p.Lys862Glu variant was identified in 8 of 111260 proband chromosomes (frequency: 0.00007) from individuals or families with breast cancer (Judkins 2005). The variant was also identified in dbSNP (ID: rs80356927) as “With Likely benign allele”, Clinvitae database (classified as benign by ClinVar; classified as likely benign by ClinVar, Invitae), Fanconi Anemia Mutation Database (LOVD), ARUP Laboratories BRCA Mutations Database (classified as not pathogenic or of no clinical significance), the ClinVar database (classified as benign by ENIGMA, Ambry genetics, SCRP; classified as likely benign by Invitae, GeneDx; classified as uncertain significance by BIC), the BIC database (5x with unknown clinical importance), and UMD (12x with a “likely neutral” classification). This variant was identified in the Exome Aggregation Consortium database (August 8th 2016) in 12 of 121328 chromosomes (freq. 0.0001) in the following populations: European in 8 of 66696 chromosomes (freq. 0.0001), Asian in 3 of 16502 chromosomes (freq. 0.0002), Finnish in 1 of 6614 chromosomes (freq. 0.0002), but was not seen in African, Latino and Other populations. The p.Lys862 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, 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, HumanSpliceFinder) do not predict a difference in splicing. The variant was also classified as neutral with odds in favor of neutrality 2059 in a study utilizing evidence of co-occurrence with a pathogenic variant, family history and if available segregation of the variant with disease (Easton 2007). The variant was also found to have a probability of being deleterious of 9.91√ó10‚à Ã6 in a similar study (Lindor 2012). In addition, a study by Burk-Herrick (2005) found the variant has no effect by analyzing 19 marsupials and 94 eutherian mammal sequences, which were used to rank oncogenic risk of missence mutations based on conservation. 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. - |
BRCA1-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 24, 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). - |
Hereditary breast ovarian cancer syndrome Benign:1
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 10, 2024 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;M;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;N;N;N;N;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;N
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D
Sift4G
Benign
T;T;T;T
Polyphen
D;.;.;P
Vest4
MVP
MPC
0.41
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
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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