Submissions for variant NM_007294.4(BRCA1):c.5506G>A (p.Glu1836Lys)

gnomAD frequency: 0.00001  dbSNP: rs80356942

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195397	SCV000077037	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-10-03	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1836 of the BRCA1 protein (p.Glu1836Lys). This variant is present in population databases (rs80356942, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 55605). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is not expected to disrupt BRCA1 function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA1 function (PMID: 20516115, 21473589, 24845084, 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.
GeneDx	RCV000168525	SCV000210229	uncertain significance	not provided	2023-06-02	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies are inconclusive: discrepant phosphopeptide binding and transcriptional activation activity, but normal protein folding, homologous recombination activity, and cell survival (Lee et al., 2010; Coquelle et al., 2011; Carvalho et al., 2014; Woods et al., 2016; Findlay et al., 2018; Fernandes et al., 2019; Petitalot et al., 2019; Iversen et al., 2022); Also known as 5625G>A; This variant is associated with the following publications: (PMID: 20159462, 14534301, 24845084, 30209399, 22154951, 28781887, 30765603, 30257991, 21473589, 20516115, 36530327, 29884841, 32377563, 35665744, 25348405)
Ambry Genetics	RCV000219922	SCV000276176	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-24	criteria provided, single submitter	clinical testing	The p.E1836K variant (also known as c.5506G>A and 5625G>A), located in coding exon 22 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5506. The glutamic acid at codon 1836 is replaced by lysine, an amino acid with similar properties. One study, which assessed the effect of BRCT missense alterations by structure and sequence based computational analysis, found this alteration to have a probability of affecting structure and function of 0.48 and 0.42, using two sets of analytic features. Additionally, refined sequence based analysis predicted this alteration to affect function (Williams RS et al. J. Biol. Chem. 2003 Dec; 278(52):53007-16). Using several different structural and functional assays, another study found this alteration to be structurally stable; however, they did predict compromised binding activity and specificity, with less than 10% of wild type for both parameters, and found transcriptional activation to be at 55% of wild type, resulting in a classification of uncertain significance for this alteration (Lee MS et al. Cancer Res. 2010 Jun; 70(12):4880-90). Additionally, while one study suggested that this alteration could perturb phosphopeptide recognition and binding (Campbell SJ et al. Structure 2010 Feb; 18(2):167-76), other studies showed that this alteration does not dramatically affect function (Coquelle N et al. Biochemistry 2011 May; 50(21):4579-89; Findlay GM et al. Nature, 2018 Oct;562:217-222). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000219922	SCV001352261	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-28	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 1836 of the BRCA1 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported discrepant findings on variant protein impacts, including modest (PMID: 21473589) to severe disruption (PMID: 20516115) in phosphopeptide binding activity, greater than 50% of wild-type transcriptional activation (PMID: 20516115), and normal function in complementing BRCA1 deficiency and rescue cell proliferation in haploid cells (PMID: 30209399). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251336 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735480	SCV003838229	uncertain significance	Breast and/or ovarian cancer	2022-09-02	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000112686	SCV004817533	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 1836 of the BRCA1 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported discrepant findings on variant protein impacts, including modest (PMID: 21473589) to severe disruption (PMID: 20516115) in phosphopeptide binding activity, greater than 50% of wild-type transcriptional activation (PMID: 20516115), and normal function in complementing BRCA1 deficiency and rescue cell proliferation in haploid cells (PMID: 30209399). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251336 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV000112686	SCV005058240	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2024-03-01	criteria provided, single submitter	clinical testing
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000112686	SCV005402709	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2024-04-12	criteria provided, single submitter	curation	Each variant was annotated with functional scores from MAVE data which was translated into functional evidence codes. All other evidence codes and combining criteria were adhered to as closely as possible based on the ClinGen VCEP (Variant Curation Expert Panel) gene-specific recommendations. See Supplemental Figure 34 of final paper (Supp Fig. 28 in preprint: doi:10.1101/2024.04.11.24305690) for a table to see which lines of evidence we did not have data for. The ClinGen VCEPs are highly regarded as the gold-standard for gene-specific variant curation and are developed after extensive evaluation of the evidence by clinical and scientific experts for the particular gene to classify genomic variants on a spectrum from pathogenic to benign using the 2015 ACMG/AMP Variant Interpretation Guidelines as a backbone (PMID: 25741868). Reclassification of these VUS variants from gnomAD or All of Us focused only on variants originally prescribed as VUS in ClinVar. To ensure reproducibility, transparency, and increased throughput, all the procedures for annotating variants and assigning evidence codes were codified using Python. All code has been made freely available and is linked in the Code Availability section and all reclassified variants with evidence codes used can be found in Tables S18-19 (preprint: doi:10.1101/2024.04.11.24305690). For the MAVE data, the clinical curation and clinical strength assignment as per the ClinGen recommendations in Brnich et al. (2020) (PMID: 31892348) for or against pathogenicity or benignity of each of these MAVE datasets utilized in this study were previously published in Fayer et al. (2021) (PMID: 34793697).In brief, for BRCA1 variants, if a variant was categorized as FUNC (functional), it was assigned BS3 evidence and no PS3 evidence, whereas if it was categorized as LOF (loss of function), the variant was assigned PS3 evidence and no BS3 evidence. Variants categorized as INT (intermediate) were left unannotated. For the BRCA1 combining criteria, greater than or equal to 1 criteria of strong benign evidence was enough to reclassify the VUS as Likely Benign. This variant GRCh37:17:41197781:C>T was assigned evidence codes ['BS3'] and an overall classification of Likely Benign
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112686	SCV000145554	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-11-25	no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735480	SCV000863617	likely benign	Breast and/or ovarian cancer	2013-06-20	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000112686	SCV001242060	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro