Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7
The NM_007294.4(BRCA1):c.5022C>T(p.Ile1674Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,452 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=-0.78).
BP6
Variant 17-43067660-G-A is Benign according to our data. Variant chr17-43067660-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 187617.Status of the report is reviewed_by_expert_panel, 3 stars.
BP7
Synonymous conserved (PhyloP=0.471 with no splicing effect.
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1Benign:4
Jul 07, 2023
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
May 24, 2017
Counsyl
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Jul 21, 2021
University of Washington Department of Laboratory Medicine, University of Washington
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
Based on functional RNA studies, the BRCA1 c.5022C>T variant was shown to disrupt splicing regulatory motifs in BRCA1 exon 17 and results in exon skipping, which leads to a premature stop codon in 32% of transcripts from the variant allele (Casadei 2019). These studies provide some evidence that this variant is pathogenic for a hypomorphic risk. Because this variant results in some full length BRCA1 transcripts, the cancer risks conferred by this variant are likely to be different than the risks associated with other pathogenic BRCA1 variants. Some literature suggests that variants like this one should be classified as variants of uncertain significance because the level of associated risk has not been established (Fraile-Bethencourt 2017). -
May 16, 2023
All of Us Research Program, National Institutes of Health
Significance: Likely benign
Review Status: criteria provided, single submitter
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/). -
not provided Benign:3
Apr 23, 2015
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Apr 27, 2021
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Nov 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
BRCA1: BP4, BP7 -
Hereditary cancer-predisposing syndrome Benign:2
Dec 19, 2014
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. -
Jun 13, 2016
Color Diagnostics, LLC DBA Color Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Hereditary breast ovarian cancer syndrome;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1
Sep 01, 2019
King Laboratory, University of Washington
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research
- -
Breast and/or ovarian cancer Uncertain:1
Oct 17, 2022
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
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
- -
BRCA1-related disorder Benign:1
May 11, 2020
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 19, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter