Submissions for variant NM_007294.4(BRCA1):c.5360G>A (p.Cys1787Tyr)

dbSNP: rs1597801649

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000820100	SCV000960794	likely pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1787 of the BRCA1 protein (p.Cys1787Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 33558524; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 662455). Advanced modeling performed at Invitae incorporating data from internal and/or published 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: 30209399). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV003442114	SCV004169414	likely pathogenic	not provided	2023-05-11	criteria provided, single submitter	clinical testing	Published functional studies suggest a damaging effect: variant classified as non-functional based on a saturation genome editing (SGE) assay measuring cell survival (Findlay et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5479G>A; This variant is associated with the following publications: (PMID: 25348405, 30209399, 33558524)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003442114	SCV004219458	likely pathogenic	not provided	2023-06-30	criteria provided, single submitter	clinical testing	The BRCA1 c.5360G>A (p.Cys1787Tyr) variant has been reported in the published literature in affected individual with early onset breast cancer (PMID: 33558524 (2021)). A saturation genome editing assay demonstrated that this variant was damaging to protein function (PMID: 30209399 (2018)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, this variant is classified as likely pathogenic.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003442114	SCV004242797	likely pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
Center of Medical Genetics and Primary Health Care	RCV001004839	SCV000987263	uncertain significance	Malignant tumor of breast	2020-06-10	no assertion criteria provided	research	ACMG Guidelines 2015 criteria This variant is in exon 21 of the BRCA1 gene in the BRCT functional domain (aa.1756-1855). This domain of about 95 amino acids is found in a large variety of proteins involved in DNA repair, recombination and cell cycle control (Bork et al., 1997). The BRCT domain is not limited to the C-terminal of protein sequences and can be found in multiple copies or in a single copy as in RAP1 and TdT. Some data indicated that the BRCT domain functions as a protein-protein interaction module (Zhang et al., 1998). This variant is found in a mutational hotspot of 33 pathogenic nonsense, and frameshift variants (PM1 Pathogenic Moderate). One different missense change at the same amino acid residue (chr17:41201185A>T (Cys1787Ser)) has been reported in ClinVar but with conflicting interpretations of pathogenicity. The variant is not found in GnomAD exomes neither in GnomAD genomes (PM2 Pathogenic Moderate). 11 pathogenic predictions from DANN, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, REVEL, SIFT, PolyPhen-2, and Align-GVGD versus 2 benign predictions from DEOGEN2 and PrimateAI support its deleterious effect (PP3 Pathogenic Supporting). This variant was found in a 31-year-old female with unilateral breast cancer and no reported family history of cancer. Based on this evidence, we classified it as a Variant of Unknown Significance.
Brotman Baty Institute, University of Washington	RCV001073117	SCV001238620	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro