Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7
The NM_007294.4(BRCA1):c.564A>G(p.Glu188Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,668 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 Likely benign (★★★).
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]
Computational evidence support a benign effect (BayesDel_noAF=-0.5).
BP6
Variant 17-43097273-T-C is Benign according to our data. Variant chr17-43097273-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 184268.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43097273-T-C is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=2.16 with no splicing effect.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing
- -
Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Aug 21, 2019
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Variant summary: BRCA1 c.564A>G alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.2e-05 in 251252 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.564A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. This variant was found in one healthy older woman in a reputed germline gnomic database (FLOSSIES). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (1x VUS, 5x Likely benign). Based on the evidence outlined above, the variant was classified as likely benign. -
not provided Uncertain:1Benign:2
Mar 05, 2018
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant is denoted BRCA1 c.564A>G at the DNA level. It is silent at the coding level, preserving a Glutamic Acid at codon 188. In silico analyses, which include splice predictors and evolutionary conservation, are uninformative in their assessment as to whether or not the variant is damaging. Using alternate nomenclature, this variant would be defined as BRCA1 683A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 c.564A>G was observed at an allele frequency of 0.007% (8/111646 alleles) in individuals of European (Non-Finnish) ancestry in large population cohorts (Lek 2016). Based on currently available evidence, it is unclear whether BRCA1 c.564A>G is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Aug 01, 2022
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
BRCA1: BP4 -
Dec 06, 2017
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1 Benign:2
Mar 02, 2020
BRCAlab, Lund University
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing
- -
Jun 29, 2017
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Significance: Likely benign
Review Status: reviewed by expert panel
Collection Method: curation
Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/). -
Hereditary cancer-predisposing syndrome Benign:2
Jul 17, 2015
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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. -
Mar 16, 2016
Color Diagnostics, LLC DBA Color Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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BRCA1-related cancer predisposition Benign:1
May 14, 2024
All of Us Research Program, National Institutes of Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Hereditary breast ovarian cancer syndrome Benign:1
Jan 08, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter