Submissions for variant NM_007294.4(BRCA1):c.1723G>A (p.Glu575Lys)

gnomAD frequency: 0.00002  dbSNP: rs397508902

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167785	SCV000075582	likely benign	Hereditary breast ovarian cancer syndrome	2023-11-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000656786	SCV000210110	uncertain significance	not provided	2019-12-03	criteria provided, single submitter	clinical testing	Observed in individuals with a personal and/or family history of breast and/or ovarian cancer; however, did not co-segregate with breast cancer in one family (Coupier 2004, Suter 2004, Anczukow 2008); Published functional studies demonstrate a damaging effect: impaired DNA break repair activity (Coupier 2004); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Also known as 1842G>A; This variant is associated with the following publications: (PMID: 25348012, 14647443, 20858050, 14973102, 23893897, 26269718, 18273839, 31825140)
Ambry Genetics	RCV000166298	SCV000217082	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-22	criteria provided, single submitter	clinical testing	The p.E575K variant (also known as c.1723G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 1723. The glutamic acid at codon 575 is replaced by lysine, an amino acid with similar properties. In one study, lymphoblast cell lines with this alteration demonstrated impaired fidelity of double strand breakage repair by DNA end-joining compared to the normal control cell line. However, the alteration did not segregate with disease in one family (Coupier I et al. Oncogene 2004 Jan; 23(4):914-9). In another study, this variant was shown to have no effect on alternate splicing using minigene splicing assay (Anczukow O et al. Genes Chromosomes Cancer. 2008; 47:418-26). An additional paper reported this alteration in 1/645 women with breast cancer from Shanghai, China (Suter NM et al, Cancer Epidemiol. Biomarkers Prev. 2004 Feb; 13(2):181-9), and in a study of 1854 high-risk breast/ovarian cancer families in Italy, this alteration was detected in 1 family (Azzollini J et al. Eur J Intern Med, 2016 Jul;32:65-71). Of note, this alteration is also designated as 1842G>A in published literature. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656786	SCV000600264	uncertain significance	not provided	2023-08-24	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported in high-risk breast and/or ovarian cancer families (PMIDs: 34981296 (2022), 31954625 (2020), 31825140 (2019), 27062684 (2016), 18273839 (2008), 14647443 (2004), 14973102 (2004)), as well as in an individual with breast cancer in a large scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA1)). This variant was also reported to be damaging to DNA break repair activity in a cell-based study (PMID: 14647443 (2004)). The frequency of this variant in the general population, 0.00002 (5/250624 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. 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, we are unable to determine the clinical significance of this variant.
Counsyl	RCV000662632	SCV000785316	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2017-07-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166298	SCV001354713	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 575 of the BRCA1 protein. Computational prediction 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). One functional study observed partial activity in an ex vivo repair assay of an extrachromosomal plasmid (PMID: 14647443). This variant has been reported in at least two unrelated individuals affected with breast cancer (PMID: 14647443, 14973102) and two suspected hereditary breast and ovarian cancer families (PMID: 27062684, 31954625). However, this variant did not segregate completely with breast cancer affected members of a family (PMID: 14647443). This variant also has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000164). This variant has been identified in 5/250624 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.
Fulgent Genetics, Fulgent Genetics	RCV002483062	SCV002787638	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2021-10-28	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000166298	SCV003851082	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
All of Us Research Program, National Institutes of Health	RCV000662632	SCV004818293	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 575 of the BRCA1 protein. Computational prediction 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). One functional study observed partial activity in an ex vivo repair assay of an extrachromosomal plasmid (PMID: 14647443). This variant has been reported in at least two unrelated individuals affected with breast cancer (PMID: 14647443, 14973102) and two suspected hereditary breast and ovarian cancer families (PMID: 27062684, 31954625). However, this variant did not segregate completely with breast cancer affected members of a family (PMID: 14647443). This variant also has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000164). This variant has been identified in 5/250624 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.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000662632	SCV003927162	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-05	no assertion criteria provided	clinical testing	a variant of uncertain significance was detected in the BRCA1 gene. The p.E575K variant (also known as c.1723G>A), located in coding region of the BRCA1 gene, results from a G to A substitution at nucleotide position 1723. The glutamic acid at codon 575 is replaced by lysine, an amino acid with similar properties. The alteration did not segregate with disease in one family (PMID 14647443). In another study, this variant was shown to have no effect on alternate splicing using minigene splicing assay (PMID 18273839). An additional paper reported this alteration in 1/645 women with breast cancer from Shanghai, China (PMID 14973102). Of note, this alteration is also designated as 1842G>A in published literature. This amino acid position is not well conserved in available vertebrate species. ClinVar has an entry for this variant with 6 submissions all of which classify it as of uncertain significance, 2 stars, no conflicts. In-silico prediction for this alteration shows Pathogenic computational verdict based on 8 pathogenic predictions from BayesDel_addAF, DANN, DEOGEN2, LIST-S2, M-CAP, MVP, MutationAssessor and SIFT vs 4 benign predictions from EIGEN, FATHMM-MKL, MutationTaster and PrimateAI. Therefore, this variant is classified as on uncertain significance. Pathogenic/Likely pathogenic BRCA1 variants cause hereditary breast/ovarian cancer syndrome (HBOC).
BRCAlab, Lund University	RCV000662632	SCV004244116	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing