Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong
The NM_007294.4(BRCA1):c.807G>A(p.Leu269Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000478 in 1,611,378 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 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=-0.47).
BP6
Variant 17-43094724-C-T is Benign according to our data. Variant chr17-43094724-C-T is described in ClinVar as [Benign]. Clinvar id is 136540.Status of the report is reviewed_by_expert_panel, 3 stars.
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. -
Benign, criteria provided, single submitter
clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Aug 15, 2023
- -
Benign, no assertion criteria provided
clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System
-
The p.Leu269Leu variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located near a splice junction, and is listed in dbSNP database (rs149867679) with a MAF score of 0.001. It was also reported in 1/111260 proband chromosomes of an individual from a HBOC family, and classified as a polymorphism in the study by Myriad; although no control chromosomes were tested to establish the variant's frequency in the general population (Judkins_2005). In addition, the variant was also identified in the UMD (x1), Exome Server and BOCs databases. In summary, based on the above information, the variant is classified as benign. -
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
May 16, 2016
- -
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Jun 03, 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
Jan 09, 2022
- -
Breast-ovarian cancer, familial, susceptibility to, 1 Benign:2
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 0.0012 (African), derived from ExAC (2014-12-17). -
Likely benign, criteria provided, single submitter
clinical testing
Counsyl
Apr 13, 2016
- -
not provided Benign:1
Benign, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Jun 21, 2023
- -
Familial cancer of breast Benign:1
Benign, criteria provided, single submitter
clinical testing
Baylor Genetics
Feb 23, 2017
- -
Hereditary breast ovarian cancer syndrome Benign:1