rs80356874
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong
The NM_007294.4(BRCA1):c.2669G>T(p.Gly890Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,613,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G890R) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000036 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 missense
NM_007294.4 missense
Scores
1
18
Clinical Significance
Conservation
PhyloP100: -1.17
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 -12 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.052277386).
BP6
Variant 17-43092862-C-A is Benign according to our data. Variant chr17-43092862-C-A is described in ClinVar as [Benign]. Clinvar id is 37479.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43092862-C-A is described in Lovd as [Benign].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.2669G>T | p.Gly890Val | missense_variant | 10/23 | ENST00000357654.9 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | ENST00000357654.9 | c.2669G>T | p.Gly890Val | missense_variant | 10/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes 0.0000329 AC: 5AN: 152026Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251020Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135654
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GnomAD4 exome AF: 0.0000363 AC: 53AN: 1461684Hom.: 0 Cov.: 51 AF XY: 0.0000303 AC XY: 22AN XY: 727132
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GnomAD4 genome 0.0000329 AC: 5AN: 152026Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4AN XY: 74244
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ClinVar
Significance: Benign
Submissions summary: Uncertain:3Benign:12
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2Benign:2
| Uncertain significance, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Nov 03, 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 = 0.00000408 - |
| Benign, criteria provided, single submitter | clinical testing | Counsyl | Apr 14, 2016 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | Feb 20, 2004 | - - |
not provided Benign:4
| Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 13, 2019 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 25, 2022 | - - |
| Likely benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 12, 2017 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 31, 2021 | This variant is associated with the following publications: (PMID: 22753008, 16267036, 11606101, 16683254, 21990134, 17924331, 12531920, 15235020) - |
Hereditary cancer-predisposing syndrome Benign:3
| Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 24, 2016 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 01, 2019 | This alteration is classified as likely 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 07, 2022 | - - |
Hereditary breast ovarian cancer syndrome Benign:2
| Benign, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Nov 16, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 19, 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.Gly890Val variant was identified in 2 of 9848 proband chromosomes (frequency: 0.0002) from individuals or families with hereditary breast and ovarian cancer (Schorge 2001, van der Hout 2006). The variant was identified in dbSNP (rs80356874) as “with uncertain significance allele”, ClinVar (classified as uncertain significance by Invitae, Sinai Health System, BIC and SCRP, likely benign by Ambry Genetics, GeneDx, ARUP and Mayo Clinic and benign by ENIGMA, Counsyl and Color) and LOVD 3.0 (observed 5x). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 5 of 251,020 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 16,254 chromosomes (freq: 0.0001), European in 3 of 113,454 chromosomes (freq: 0.00003), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish, Other and South Asian populations. The p.Gly890Val 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 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this 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. This variant is classified as a variant of uncertain significance. - |
not specified Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 20, 2024 | Variant summary: BRCA1 c.2669G>T (p.Gly890Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251020 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2669G>T has been reported in affected individuals via publications with no co-segregation information to rule in or rule out causation. In particular, the variant has been reported (Schorge_2001) in one family to be present in an unaffected individual. No details about the nature or extent of family member testing (i.e., co-segregation) were provided. Authors called this variant as a polymorphism. 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). The following publications have been ascertained in the context of this evaluation (PMID: 16267036, 15385441, 21990134, 15235020, 17924331, 12531920, 15001988, 22753008, 16683254, 11606101, 25782689, 29580235, 26094954, 33471991). ClinVar contains an entry for this variant (Variation ID: 37479). Based on the evidence outlined above, the variant was classified as likely benign. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T;T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;N;.;.
MutationTaster
Benign
N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;N
REVEL
Uncertain
Sift
Benign
T;T;T;T
Sift4G
Benign
T;T;T;T
Polyphen
B;.;.;B
Vest4
MVP
MPC
0.11
ClinPred
T
GERP RS
RBP_binding_hub_radar
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Varity_R
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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