Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_007294.4(BRCA1):c.5236C>G(p.His1746Asp) 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 Likely pathogenic (★★★). 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: Pathogenic. The variant received 16 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-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 433726.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.89
PP5
Variant 17-43057093-G-C is Pathogenic according to our data. 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.
Hereditary breast ovarian cancer syndromePathogenic:1Uncertain:1
Nov 14, 2023
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:curation
PS3, PM2_sup, PP3. According to the ClinGen ENIGMA BRCA1 v1.0.0 criteria we chose these criteria: PS3 (strong pathogenic): PS3_strong:Table 9: Reported by two calibrated studies to affect protein function similar to pathogenic control variants (PMIDs:30209399, Findlay, 30765603, Fernandes), PM2 (supporting pathogenic): Absent from gnomAD PM2_supp, PP3 (supporting pathogenic): BayesDel noAF score 0.3731 -
Sep 28, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 1746 of the BRCA1 protein (p.His1746Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ovarian cancer (PMID: 25036526). ClinVar contains an entry for this variant (Variation ID: 531399). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 11877378, 30209399, 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. -
The p.H1746D variant (also known as c.5236C>G), located in coding exon 18 of the BRCA1 gene, results from a C to G substitution at nucleotide position 5236. The histidine at codon 1746 is replaced by aspartic acid, an amino acid with similar properties. This variant has been reported in an individual diagnosed with ovarian cancer and in a cohort of Chinese individuals who underwent multi-gene panel testing for HBOC risk assessment (Gleicher N et al. PLoS One, 2014 Jul;9:e102370; Shao D et al. Cancer Sci, 2020 Feb;111:647-657). One functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). A transcriptional activation assay found that this variant had <80% activity relative to wildtype and was, thus, considered deleterious (Fernandes VC et al. J Biol Chem, 2019 04;294:5980-5992). This variant was also reported as non-functional in a homology directed repair assay, but functional in an assay of cisplatin resistance (Adamovich AI et al. Am J Hum Genet. 2022 Apr;109(4):618-630). Based on internal structural analysis, this variant is anticipated to result in a decrease in structural stability (Ambry internal data; Wu Q et al. Mol Cell, 2016 Feb;61:434-448). 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. -
not providedUncertain:1
Oct 21, 2022
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in an individual with ovarian cancer (PMID: 25036526 (2014)). Functional studies are supportive of a damaging effect on protein function (PMIDs: 30765603 (2019), 30209399 (2018), 11877378 (2002)), however additional studies are needed to determine the global effect of this variant on BRCA1 protein function. 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
BRCA1-related disorderUncertain:1
Sep 18, 2024
PreventionGenetics, part of Exact Sciences
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing
The BRCA1 c.5236C>G variant is predicted to result in the amino acid substitution p.His1746Asp. This variant has been reported in individuals with a history of ovarian cancer (Table 3, Gleicher et al. 2014. PubMed ID: 25036526), and was reported as uncertain with a high level of evidence in a cohort of Chinese individuals who underwent testing for high risk hereditary breast and ovarian cancer risk assessment (Table S2, Shao et al. 2019. PubMed ID: 31742824). Functional studies indicate this variant reduces BRCA1-BACH1 binding (Joo et al. 2002. PubMed ID: 11877378). Additional functional studies demonstrated that this variant had an intermediate effect on protein function (Supplemental Table 1, Findlay et al. 2018. PubMed ID: 30209399), and another study showed that this variant demonstrated markedly reduced reporter transcription activation function relative to wild type in vitro and was considered deleterious (Table S2, Fernandes et al. 2019. PubMed ID: 30765603). To our knowledge, this variant has not been reported in a large population database, indicating this variant is rare. This variant has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain to likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/531399/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -