Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7
The NM_007294.4(BRCA1):c.3012G>A(p.Glu1004Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,864 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=-0.82).
BP6
Variant 17-43092519-C-T is Benign according to our data. Variant chr17-43092519-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 184912.Status of the report is reviewed_by_expert_panel, 3 stars.
BP7
Synonymous conserved (PhyloP=-0.352 with no splicing effect.
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Mar 04, 2016
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant is denoted BRCA1 c.3012G>A at the DNA level. This variant is silent at the coding level, preserving a Glutamic Acid at codon 1004. Using alternate nomenclature, this variant would be defined as BRCA1 3131G>A. It is not predicted to cause abnormal splicing. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 c.3012G>A was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.The nucleotide which is altered, a guanine (G) at base 3012, is conserved in mammals. Based on currently available information, it is unclear whether BRCA1 c.3012G>A is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Jun 24, 2022
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Hereditary cancer-predisposing syndrome Benign:3
Feb 13, 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. -
Aug 14, 2018
Color Diagnostics, LLC DBA Color Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Oct 08, 2021
Sema4, Sema4
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: curation
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Breast-ovarian cancer, familial, susceptibility to, 1 Benign:2
May 28, 2019
Mendelics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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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/). -
not specified Benign:1
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
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BRCA1-related disorder Benign:1
Mar 01, 2019
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing
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
Jan 30, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter