rs28897684
Positions:
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4BP6_Very_Strong
The NM_007294.4(BRCA1):c.2525A>G(p.Glu842Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,613,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. ET842G?) has been classified as Pathogenic.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000041 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 missense
NM_007294.4 missense
Scores
1
9
9
Clinical Significance
Conservation
PhyloP100: 1.89
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=0.34768695).
BP6
Variant 17-43093006-T-C is Benign according to our data. Variant chr17-43093006-T-C is described in ClinVar as [Benign]. Clinvar id is 91592.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43093006-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.2525A>G | p.Glu842Gly | 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.2525A>G | p.Glu842Gly | missense_variant | 10/23 | 1 | NM_007294.4 | ENSP00000350283 | P4 |
Frequencies
GnomAD3 genomes 0.0000197 AC: 3AN: 152228Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251106Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135736
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GnomAD4 exome AF: 0.0000411 AC: 60AN: 1461576Hom.: 0 Cov.: 43 AF XY: 0.0000371 AC XY: 27AN XY: 727074
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GnomAD4 genome 0.0000197 AC: 3AN: 152228Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74378
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ClinVar
Significance: Benign
Submissions summary: Benign:13
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Benign:3
| Benign, criteria provided, single submitter | clinical testing | Counsyl | Dec 04, 2015 | - - |
| 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 = 0.0000043 - |
| Benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | May 01, 2012 | - - |
Hereditary cancer-predisposing syndrome Benign:3
| Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 21, 2016 | - - |
| 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 | curation | Sema4, Sema4 | Feb 24, 2022 | - - |
not specified Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 10, 2017 | - - |
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 30, 2021 | Variant summary: BRCA1 c.2525A>G (p.Glu842Gly) results in a non-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 1.2e-05 in 251106 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2525A>G was originally reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Judkins_2005, Cecener_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. The variant has been reported in the FLOSSIES database in two women older than age 70 years who have never had cancer, providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Studies utilizing multifactorial likelihood models to assess the clinical significance of BRCA1 variants predict this variant to be neutral/not pathogenic (Lindor_2012, Easton_2007). Six ClinVar submissions from clinical diagnostic laboratories and an expert panel (ENIGMA) (evaluation after 2014) cite the variant as likely benign (n=2) and benign (n=5, including ENIGMA). All submitters have utilized the same/overlapping sources of evidence utilized in this evaluation. Based on the evidence outlined above, the variant was classified as benign. - |
not provided Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 23, 2019 | This variant is associated with the following publications: (PMID: 21990134, 16267036, 25348012, 17924331, 17719744) - |
| Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.Glu842Gly variant was identified in the literature with conflicting interpretations of pathogenicity based on predictive computational models, neutral (Lindor 2012, Easton 2007) and variant of unknown significance (Judkins 2005). The variant was also identified in dbSNP (ID: rs28897684) “With Uncertain significance allele”, Clinvitae database (classifications: benign and likely benign), Fanconi Anemia Mutation Database (unclassified), LOVD-IARC database (classified as not pathogenic), ARUP Laboratories BRCA Mutations Database (classification not pathogenic or of no clinical significance), the ClinVar database (classifications: benign by ENIGMA, Ambry Genetics and Sharing Clinical Reports Project), derived from Myriad reports; likely benign by Invitae; and uncertain significance by Molecular Genetics Diagnostic Laboratory-CHEO), UMD (2x with a “neutral” classification), and the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in the European (Non-Finnish) population in 2 of 66712 alleles (frequency: 0.00003), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Glu842 residue is conserved in mammals but not in more distantly related organisms 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, HumanSpliceFinder) do not predict a difference in splicing; this information is not very predictive of pathogenicity. 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. - |
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 10, 2022 | - - |
Inherited breast cancer and ovarian cancer Benign:1
| Benign, criteria provided, single submitter | clinical testing | Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service | May 23, 2024 | BP1,BP5_Very Strong - |
Hereditary breast ovarian cancer syndrome Benign:1
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 11, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T;T;T
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.;.
MutationTaster
Benign
N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
P;.;.;D
Vest4
MVP
MPC
0.30
ClinPred
T
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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