Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6
The NM_007294.4(BRCA1):c.4565A>G(p.Tyr1522Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. Y1522H) has been classified as Uncertain significance.
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]
BRCA1 Gene-Disease associations (from GenCC):
breast-ovarian cancer, familial, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Our verdict: Likely_benign. The variant received -1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06831592).
BP6
Variant 17-43074441-T-C is Benign according to our data. Variant chr17-43074441-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 55228.
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 specifiedUncertain:1
Feb 06, 2020
Genetic Services Laboratory, University of Chicago
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
DNA sequence analysis of the BRCA1 gene demonstrated a sequence change, c.4565A>G, in exon 14 that results in an amino acid change, p.Tyr1522Cys. This sequence change has not been described in population databases (gnomAD, ExAC). Functional studies demonstrated no impact on protein function in the presence of this sequence change (PMID: 28781887). The p.Tyr1522Cys change affects a poorly conserved amino acid residue located in a domain of the BRCA1 protein that is known to be functional. The p.Tyr1522Cys substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences, the clinical significance of the p.Tyr1522Cys change remains unknown at this time. -
Breast-ovarian cancer, familial, susceptibility to, 1Uncertain:1
May 29, 2002
Breast Cancer Information Core (BIC) (BRCA1)
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing
- -
Hereditary breast ovarian cancer syndromeUncertain:1
Sep 30, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1522 of the BRCA1 protein (p.Tyr1522Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 19190334). ClinVar contains an entry for this variant (Variation ID: 55228). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 30765603). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -