Submissions for variant NM_007294.4(BRCA1):c.5363G>A (p.Gly1788Asp)

dbSNP: rs80357069

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077620	SCV001161715	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2019-03-25	reviewed by expert panel	curation	To our knowledge this variant has only been seen alone once, in a male control in gnomAD (South Asian population). Clinical evidence in Goldgar et al 2004 (PMID: 15290653) is not applicable unless this variant is observed in cis with c.5359T>A (Variation ID 55548). We recommend that if c.5363G>A is detected in an individual, presence of c.5359T>A should be assessed. Functional assay data analysis of the c.5363G>A variant suggests that it is unlikely to alter protein function alone, but that it does alter function when in combination with BRCA1 c.5359T>A (PMID: 30765603; 30209399). For more information see the haplotype entry BRCA1 c.[5359T>A;5363G>A] (Variant ID 624568).
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	RCV001542250	SCV001760922	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-07-09	criteria provided, single submitter	reference population	Data included in classification: Prevalence in cases vs controls is increased (PS4_sup) Absent from non-cancer females in gnomAD (PM2_mod). Critical residue within BRCT domain (PM1_mod). REVEL 0.862 (PP3_sup). Parsons et al, 2019 combined LR: 0.0457 (BP6_str). Data not included in classification: Conflicting functional data: Lee et al 2010 PMID: 20516115 = VUS Gaboriau et al 2015 PMID: 25748678 = 30-50% HR activity (VUS) Woods et al 2016 PMID: 28781887 = VUS Findlay et al 2018 PMID: 30209399 = FUNC (G1788V & G1788C both LOF), Bouwman et al 2020 PMID: 32546644 = Cisplatin NEUTRAL, Olaparib DEL, DR-GFP DEL G1788C and G1788V (class 5) also reported at this position (PM5 not applied due to conflicting functional data and PM1 already having been applied)
Revvity Omics, Revvity	RCV001781378	SCV002022078	likely pathogenic	not provided	2019-05-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003584537	SCV004360114	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-25	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with aspartic acid at codon 1788 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies reported this variant as normal compared to wild-type control in transcription activation, haploid cell proliferation, protein stability and peptide binding assays (PMID: 20516115, 21447777, 30209399). This variant has been reported in cis with BRCA1 p.Cys1887Ser in several individuals and families affected with breast and/or ovarian cancer (PMID: 16030099, 18284688, 23233716, 25628955 , 26543556, 28959512). This variant has been observed in cis with BRCA1 p.Cys1787Ser and cosegregated with disease (PMID: 15290653, 25628955). A multifactorial analysis reported a likelihood ratio for pathogenicity based on case-control data of 0.04567 (PMID: 31131967). Other missense variants this codon (ClinVar variation ID: 37660, 55550, 531438) and codon 1787 (ClinVar variation ID: 662455) are considered likely disease-causing, suggesting that glycine or similar amino acid at this codon is important for the protein function. This variant has been identified in 1/251442 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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.
Ambry Genetics	RCV003584537	SCV005026085	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-10	criteria provided, single submitter	clinical testing	The p.G1788D variant (also known as c.5363G>A), located in coding exon 20 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5363. The glycine at codon 1788 is replaced by aspartic acid, an amino acid with similar properties. One functional study found that this nucleotide substitution is functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Conversely, this variant had 25.03% of wildtype activity in a transcription activation assay (Woods NT et al. NPJ Genom Med, 2016 Mar;1:). Based on internal structural assessment G1788 alterations are expected to cause general structural disruption of the BRCT domain (Clapperton JA et al. Nat Struct Mol Biol, 2004 Jun;11:512-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000077620	SCV005398899	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Fanconi anemia, complementation group S (MIM#617883), and susceptibility to breast and ovarian cancer (MIM#604370). (I) 0112 - The condition associated with this gene has incomplete penetrance. The highest estimate for cancer risk in carriers of pathogenic variants is 80% by the age of 70 years (PMID: 30551077). (I) 0108 - Autosomal recessive inheritance of variants is associated with fanconi anaemia, complementation group S (MIM#617883). Autosomal dominant inheritance is associated with an increased risk for familial breast and/or ovarian cancer, 1 (MIM#604370) and pancreatic cancer susceptibility, 4 (MIM#614320) (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated BRCT2 domain (Uniprot). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported multiple times as a VUS in ClinVar and once as Pathogenic. It has been curated as a VUS by the ENIGMA expert panel (PMID: 31131967). This variant is often observed as a haplotype with p.(Cys1787Ser), this haplotype has been classified as pathogenic by ENIGMA (ClinVar, PMID: 31131967, PMID: 33087888, PMID: 15290653, PMID: 16030099). (I) 1003 - This variant has strong functional evidence supporting normal protein function. Functional assay data analysis of this variant suggests that it is unlikely to alter protein function alone, but that it does alter function when in combination with p.(Cys1787Ser) (PMID: 28781887, PMID: 30765603, PMID: 30209399, PMID: 33087888). (SB) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000077620	SCV005402693	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 GRCh37:17:41201181:C>T was assigned evidence codes ['BS3'] and an overall classification of Likely Benign
Sharing Clinical Reports Project (SCRP)	RCV000077620	SCV000109423	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2008-04-07	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077620	SCV000145481	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496269	SCV000587503	uncertain significance	not specified	2014-01-31	no assertion criteria provided	research
Brotman Baty Institute, University of Washington	RCV000077620	SCV001242677	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro