Submissions for variant NM_007294.4(BRCA1):c.5236C>G (p.His1746Asp)

dbSNP: rs80357146

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637721	SCV000759194	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-09-28	criteria provided, single submitter	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.
Ambry Genetics	RCV002334088	SCV002645354	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-12-02	criteria provided, single submitter	clinical testing	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003478362	SCV004219448	uncertain significance	not provided	2022-10-21	criteria provided, single submitter	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.
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000637721	SCV004227976	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-14	criteria provided, single submitter	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
Brotman Baty Institute, University of Washington	RCV001072554	SCV001237959	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
PreventionGenetics, part of Exact Sciences	RCV004731003	SCV005338493	uncertain significance	BRCA1-related disorder	2024-09-18	no assertion criteria provided	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.