Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_ModerateBP6_Very_Strong
The NM_007294.4(BRCA1):c.593+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,613,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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=-0.37).
BP6
Variant 17-43097241-C-T is Benign according to our data. Variant chr17-43097241-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 91657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Benign:4
Likely benign, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health
Jan 11, 2024
- -
Likely benign, no assertion criteria provided
clinical testing
BRCAlab, Lund University
Mar 02, 2020
- -
Uncertain significance, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
Nov 14, 1997
- -
Likely benign, no assertion criteria provided
clinical testing
Sharing Clinical Reports Project (SCRP)
May 01, 2012
- -
Likely benign, criteria provided, single submitter
clinical testing
Counsyl
Jul 14, 2017
- -
not specified Benign:3
Likely benign, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Sep 26, 2019
Variant summary: BRCA1 c.593+3G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. This prediction has been confirmed by a functional study (Leman_2018). The variant allele was found at a frequency of 2.8e-05 in 251310 control chromosomes, predominantly within the African or African-American subpopulation at a frequency of 0.00043 in the gnomAD database. 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.593+3G>A in individuals affected with Hereditary Breast and Ovarian Cancer has been reported. Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.2092delC (p.Leu698TyrfsX32), UMD), providing supporting evidence for a benign role. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All 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
GeneDx
Aug 29, 2014
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
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Sep 15, 2016
- -
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Jan 29, 2018
- -
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Nov 05, 2018
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
Nov 01, 2021
- -
Hereditary breast ovarian cancer syndrome Benign:2
Benign, criteria provided, single submitter
clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State
Apr 19, 2022
- -
Likely benign, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Jan 08, 2024
- -
not provided Benign:1
Benign, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano