Submissions for variant NM_007294.4(BRCA1):c.4903G>A (p.Glu1635Lys)

gnomAD frequency: 0.00001  dbSNP: rs200432771

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000410023	SCV000489521	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-10-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000509803	SCV000608213	likely benign	Hereditary cancer-predisposing syndrome	2021-02-17	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769712	SCV000901132	uncertain significance	Breast and/or ovarian cancer	2021-09-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001071216	SCV001236507	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-04-22	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 1635 of the BRCA1 protein (p.Glu1635Lys). This variant is present in population databases (rs200432771, gnomAD 0.0009%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 21218378). ClinVar contains an entry for this variant (Variation ID: 41829). 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 with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 30209399). 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	RCV000034755	SCV002820826	uncertain significance	not provided	2022-07-13	criteria provided, single submitter	clinical testing	Published functional studies demonstrate no damaging effect: variant classified as functional based on a saturation genome editing (SGE) assay measuring cell survival (Findlay et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Observed in an individual with ovarian cancer (Carney et al., 2010); Also known as 5022G>A; This variant is associated with the following publications: (PMID: 22703879, 30209399, 31131967, 21218378)
Baylor Genetics	RCV000410023	SCV004212695	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2024-03-17	criteria provided, single submitter	clinical testing
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000410023	SCV005402494	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 GRCh38:17:43071011:C>T was assigned evidence codes ['BS3', 'BP1_Strong'] and an overall classification of Benign
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034755	SCV000043154	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Brotman Baty Institute, University of Washington	RCV000410023	SCV001243813	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
PreventionGenetics, part of Exact Sciences	RCV004758618	SCV005362629	uncertain significance	BRCA1-related disorder	2024-06-12	no assertion criteria provided	clinical testing	The BRCA1 c.4903G>A variant is predicted to result in the amino acid substitution p.Glu1635Lys. This variant was observed in a patient with ovarian cancer (Table 1. Carney ME et al 2010. PubMed ID: 21218378). This variant was also reported in a patient with polyps who had a family history of pancreas cancer, colorectum, other GI cancer, polyps, and melanoma. This individual also carried  MSH6, PTEN, and BMPR1A variants (Table. S4 Bhai et al 2021. PubMed ID: 34326862). Functional studies have shown that this variant does not disrupt the function of BRCA1 (Johnston JJ et al. 2012. PubMed ID: 22703879). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting classifications of pathogenicity in ClinVar ranging from likely benign to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/41829/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.