Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong
The ENST00000478531.6(BRCA1):c.784+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000416 in 1,610,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as 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]
BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.5).
BP6
?
BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 17-43094736-A-G is Benign according to our data. Variant chr17-43094736-A-G is described in ClinVar as [Benign]. Clinvar id is 55708.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43094736-A-G is described in Lovd as [Likely_benign]. Variant chr17-43094736-A-G is described in Lovd as [Benign].
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Benign:2
Uncertain significance, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
Sep 18, 2010
- -
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 alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/) and frequency 0.0031 (East Asian), derived from ExAC (2014-12-17). -
Likely benign, criteria provided, single submitter
clinical testing
Counsyl
Feb 20, 2018
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Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Feb 17, 2016
- -
Likely benign, criteria provided, single submitter
curation
Sema4, Sema4
Dec 15, 2021
- -
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Sep 30, 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. -
not provided Benign:2
Likely benign, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Feb 21, 2017
Variant summary: The BRCA1 795T>C (p.Ser265Ser) variant causes a synonymous change involving the alteration of a conserved nucleotide, which 5/5 splice prediction tools predict no significant impact on normal splicing. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 27/121032 (1/4482), predominantly in the East Asian cohort, 27/8652 (1/320), which does exceed the estimated maximal expected allele frequency for a pathogenic BRCA1 variant of 1/1000. Therefore, suggesting the variant is a benign polymorphism found in population(s) of East Asian origin. A functional study, Raponi_2012 reports that the variant could influence the use of an alternative splice site reducing the D(11a) isoform, however, this functional experiment alone is not sufficient evidence to suggest pathogenicity. In addition, Thirthagiri_2008 and Judkins_2005, along with multiple clinical diagnostic laboratories classify the variant as "likely benign/benign/polymorphism." Taken together, this variant is classified as a "likely benign." -
Benign, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Nov 25, 2022
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not specified Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency
Apr 18, 2017
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BRCA1-related disorder Benign:1
Likely benign, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
Oct 26, 2022
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