Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2BP4_StrongBP6_Very_StrongBP7
The NM_007294.4(BRCA1):c.1788C>T(p.Leu596Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,698 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]
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.8).
BP6
Variant 17-43093743-G-A is Benign according to our data. Variant chr17-43093743-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 427314.Status of the report is reviewed_by_expert_panel, 3 stars.
BP7
Synonymous conserved (PhyloP=-1.3 with no splicing effect.
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Mar 23, 2020
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. -
Oct 06, 2024
Molecular Diagnostics Laboratory, Catalan Institute of Oncology
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
BP1_Strong c.1788C>T, located outside any (potentially) clinically important functional domain of BRCA1, is predicted to result in no splicing alteration (according to SpliceAI) and no amino acid change, p.(Leu596=) (BP1_Strong). This variant is found in 2/267952 alleles at a frequency of 0.0008% in the gnomAD v2.1.1 database, non-cancer dataset. To our knowledge, neither relevant clinical data nor well-stablished functional studies have been reported for this variant. In addition, it has been identified in the ClinVar database (6x likely benign) and BRCA Exchange database (Likely benign: Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration), but it is not present in the LOVD database. Based on the currently available information, c.1788C>T is classified as a likely benign variant according to ClinGen-BRCA1 Guidelines version v1.0.0. -
not provided Benign:2
Jan 21, 2020
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Oct 02, 2018
GeneDx
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:1
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 breast ovarian cancer syndrome Benign:1
Nov 15, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter