Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4_StrongBP6
The ENST00000357654.9(BRCA1):āc.5176A>Gā(p.Arg1726Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000219 in 1,458,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1726I) has been classified 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]
Verdict is Likely_benign. Variant got -3 ACMG points.
PM1
In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 9 benign, 17 uncertain in ENST00000357654.9
BP4
Computational evidence support a benign effect (MetaRNN=0.060319573).
BP6
Variant 17-43063350-T-C is Benign according to our data. Variant chr17-43063350-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 55443.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1, Likely_benign=6, not_provided=1}.
Likely benign, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Feb 21, 2023
- -
Likely benign, criteria provided, single submitter
clinical testing
CeGaT Center for Human Genetics Tuebingen
Oct 01, 2020
- -
Uncertain significance, criteria provided, single submitter
clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Nov 03, 2021
- -
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Benign:1Other:1
Uncertain significance, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
Jun 20, 2002
- -
Benign, no assertion criteria provided
clinical testing
Sharing Clinical Reports Project (SCRP)
May 01, 2012
- -
not provided, no classification provided
in vitro
Brotman Baty Institute, University of Washington
-
- -
Hereditary cancer-predisposing syndrome Benign:3
Benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Jun 02, 2014
This alteration is classified as 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
Mar 24, 2021
- -
Benign, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
May 02, 2017
- -
not specified Benign:1
Likely benign, criteria provided, single submitter
clinical testing
GeneDx
Jul 06, 2017
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. -
Breast and/or ovarian cancer Benign:1
Likely benign, criteria provided, single submitter
clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Feb 22, 2023
- -
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter