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

dbSNP: rs80357069

Total submissions: 8

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.
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