Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5
The NM_007294.4(BRCA1):c.5236C>T(p.His1746Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. H1746Q) 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_pathogenic. The variant received 9 ACMG points.
PM1
In a hotspot region, there are 27 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 63 uncertain in NM_007294.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-43057093-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 531399.Status of the report is reviewed_by_expert_panel, 3 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.859
PP5
Variant 17-43057093-G-A is Pathogenic according to our data. Variant chr17-43057093-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 433726.
The p.H1746Y variant (also known as c.5236C>T), located in coding exon 18 of the BRCA1 gene, results from a C to T substitution at nucleotide position 5236. The histidine at codon 1746 is replaced by tyrosine, an amino acid with similar properties. One functional study found that this nucleotide substitution is non-functional in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 Oct;562:217-222). Another variant at the same codon, p.H1746D (c.5236C>G), has been described as deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Breast-ovarian cancer, familial, susceptibility to, 1Uncertain:1
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Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing
The BRCA1 p.His1746Tyr variant has not been previously reported. The p.His1746 residue is conserved across mammals and lower organisms and computational analyses (PolyPhen2, SIFT, AlignGVGD) suggest that the variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in-silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) does not predict a difference in splicing. Another missense alteration at the same amino acid position (c.5236C>A, p.His1746Asn) has been reported in HGMD, UMD, BIC, and LOVD with unknown clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined at this time. Therefore this variant is classified as a variant of unknown significance. -
Breast and/or ovarian cancerUncertain:1
Apr 08, 2013
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing
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not providedUncertain:1
Jun 13, 2024
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
The BRCA1 c.5236C>T (p.His1746Tyr) variant has been reported in one functional study using a haploid cell line as having lost functional activity (PMID: 30209399 (2018)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -