Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7
The NM_007294.4(BRCA1):c.5100A>G(p.Thr1700Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,613,968 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=-0.6).
BP6
Variant 17-43063926-T-C is Benign according to our data. Variant chr17-43063926-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 184204.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43063926-T-C is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-0.673 with no splicing effect.
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Dec 09, 2014
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
Oct 07, 2021
- -
Likely benign, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Dec 02, 2015
- -
Breast-ovarian cancer, familial, susceptibility to, 1 Benign:2Other:1
not provided, no classification provided
in vitro
Brotman Baty Institute, University of Washington
-
- -
Likely benign, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health
Feb 05, 2024
- -
Likely benign, reviewed by expert panel
curation
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Jun 29, 2017
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:2
Benign, criteria provided, single submitter
clinical testing
GeneDx
Apr 27, 2015
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Sep 22, 2020
- -
Malignant tumor of breast Benign:1
Likely benign, no assertion criteria provided
clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System
-
The p.Thr1700Thr variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located near a splice junction. It has not been previously identified by our laboratory, but has been reported in the literature in a study involving 55,630 probands (frequency was not provided) from families with familiar breast and ovarian cancers, and classified as a variant of benign significance. In addition, no control chromosomes were tested to establish the frequency of the variant in the general population (Judkins 2005). This variant is listed in the dbSNP database (ID#:rs45519437) but no frequency information was provided, and so the prevalence of this variant in the population is not known. The variant was also identified in the UMD database (2x) and once in the presence of a second unclassified variant, although this does not provide any additional clarification as to the clinical significance of this variant. In summary, based on the above information, this variant is predicted benign. -
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter