Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6
The NM_007294.4(BRCA1):c.1775G>A(p.Ser592Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,696 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).
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 -1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.071383625).
BP6
Variant 17-43093756-C-T is Benign according to our data. Variant chr17-43093756-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 186563.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3}.
University of Washington Department of Laboratory Medicine, University of Washington
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: curation
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
Dec 31, 2018
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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. -
Feb 28, 2023
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This missense variant replaces serine with asparagine at codon 592 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has reported that this variant results in intermediate activity in a number of yeast homology-mediated repair associated assays and a small colony phenotype assay (PMID: 35409408). This variant has been reported in a family suspected to be affected with hereditary cancer (PMID: 31853058). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2
May 28, 2019
Mendelics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Jun 28, 2023
All of Us Research Program, National Institutes of Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This missense variant replaces serine with asparagine at codon 592 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a family suspected to be affected with hereditary cancer (PMID: 31853058). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
not provided Benign:1
-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing
- -
Hereditary breast ovarian cancer syndrome Benign:1
Nov 10, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Loss of phosphorylation at S592 (P = 0.0352);Loss of phosphorylation at S592 (P = 0.0352);.;Loss of phosphorylation at S592 (P = 0.0352);.;Loss of phosphorylation at S592 (P = 0.0352);.;