Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_007294.4(BRCA1):c.290C>T(p.Thr97Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T97T) 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]
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Variant summary: The BRCA1 c.290C>T variant affects a conserved nucleotide, resulting in an amino acid change from Thr to Ile. 4/5 in-silico tools predict this variant to be damaging. This variant was not found in 121310 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available. -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The p.T97I variant (also known as c.290C>T), located in coding exon 4 of the BRCA1 gene, results from a C to T substitution at nucleotide position 290. The threonine at codon 97 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. One functional study found that this nucleotide substitution has intermediate function in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 Oct;562:217-222). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -
Hereditary breast ovarian cancer syndrome Uncertain:1
Jul 06, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA1 function (PMID: 30209399, 32546644). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) did not meet the statistical confidence thresholds required to predict the impact of this variant on BRCA1 function. ClinVar contains an entry for this variant (Variation ID: 133721). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 97 of the BRCA1 protein (p.Thr97Ile). 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. -
not specified Other:1
Sep 19, 2013
ITMI
Significance: not provided
Review Status: no classification provided
Collection Method: reference population
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Breast-ovarian cancer, familial, susceptibility to, 1 Other:1
Loss of phosphorylation at Y101 (P = 0.1484);Loss of phosphorylation at Y101 (P = 0.1484);Loss of phosphorylation at Y101 (P = 0.1484);Loss of phosphorylation at Y101 (P = 0.1484);.;Loss of phosphorylation at Y101 (P = 0.1484);.;Loss of phosphorylation at Y101 (P = 0.1484);.;.;Loss of phosphorylation at Y101 (P = 0.1484);Loss of phosphorylation at Y101 (P = 0.1484);Loss of phosphorylation at Y101 (P = 0.1484);.;Loss of phosphorylation at Y101 (P = 0.1484);Loss of phosphorylation at Y101 (P = 0.1484);.;.;