Submissions for variant NM_007294.4(BRCA1):c.4054G>A (p.Glu1352Lys)

gnomAD frequency: 0.00002  dbSNP: rs80357202

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132305	SCV000187391	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-16	criteria provided, single submitter	clinical testing	The p.E1352K variant (also known as c.4054G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 4054. The glutamic acid at codon 1352 is replaced by lysine, an amino acid with similar properties. In one study of breast-ovarian cancer families in Sardinia, this variant was observed in at least one family (Palomba G et al. BMC Cancer 2009 ; 9:245). This alteration was also detected in 1/1854 high-risk breast and/or ovarian cancer families in one study (Azzollini J et al. Eur. J. Intern. Med., 2016 Jul;32:65-71) and in 1/1045 patients with breast and/or ovarian cancer in another study (Zuntini R et al. Front Genet, 2018 Sep;9:378). In another study that used functional data combined with a model to predict the likelihood of pathogenicity, this alteration was classified as a variant of uncertain significance (Woods NT et al. NPJ Genom Med, 2016 Mar;1:). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000132305	SCV000905030	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-28	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 1352 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have been reported that this variant does not impact BRCA1 function in transcript activation assays and in a homology-directed DNA repair assay in mouse Brca1-deficient embryonic stem cells (PMID: 28781887, 29884841, 32546644). This variant has been reported in four individuals affected with breast or ovarian cancer (PMID: 19619314, 32438681, 32854451; the Leiden Open Variation Database-individual #00145597) and in at least three families affected with breast and ovarian cancer with segregation likelihood ratio of 3.49 in one family (PMID: 30254663, 31131967). 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_002200). This variant has been identified in 6/251066 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001351578	SCV001546067	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-09-29	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 1352 of the BRCA1 protein (p.Glu1352Lys). 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. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 23704879, 32546644). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function. ClinVar contains an entry for this variant (Variation ID: 55089). This missense change has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 17216544, 27062684, 30254663, 32438681, 32854451, 34178674). This variant is present in population databases (rs80357202, gnomAD 0.005%).
University of Washington Department of Laboratory Medicine, University of Washington	RCV000132305	SCV003846341	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).
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112235	SCV000144949	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-11-25	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001729372	SCV001978507	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001729372	SCV001979348	uncertain significance	not provided		no assertion criteria provided	clinical testing
Department of Medical and Surgical Sciences, University of Bologna	RCV000112235	SCV004228356	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-09-01	no assertion criteria provided	clinical testing	BS1(Supporting)+BS3(Strong)+BP5(Moderate) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)