Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2BP4_StrongBP6_Very_StrongBP7
The ENST00000357654.9(BRCA1):c.5388A>G(p.Ser1796=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,614,126 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. S1796S) has been classified as Uncertain significance.
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=-0.78).
BP6
Variant 17-43049139-T-C is Benign according to our data. Variant chr17-43049139-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 184087.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43049139-T-C is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-0.934 with no splicing effect.
Likely benign, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Dec 04, 2018
Variant summary: BRCA1 c.5388A>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 1.2e-05 in 246234 control chromosomes. 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.5388A>G in individuals affected with Hereditary Breast and Ovarian Cancer has been reported. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Jan 25, 2021
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Breast-ovarian cancer, familial, susceptibility to, 1 Benign:1Other:1
not provided, no classification provided
in vitro
Brotman Baty Institute, University of Washington
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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/). -
BRCA1-related cancer predisposition Benign:1
Likely benign, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health
Jun 09, 2024
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Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Dec 16, 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. -
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter