Submissions for variant NM_007294.4(BRCA1):c.1618G>A (p.Glu540Lys)

dbSNP: rs730881471

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159954	SCV000210106	uncertain significance	not provided	2018-02-12	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.1618G>A at the cDNA level, p.Glu540Lys (E540K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAG>AAG). Using alternate nomenclature, this variant would be defined as BRCA1 1737G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Glu540Lys was not observed in large population cohorts (Lek 2016). This variant is located in the DNA binding domain and in a region known to interact with multiple other proteins (Narod 2004, Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Glu540Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000775176	SCV000909371	uncertain significance	Hereditary cancer-predisposing syndrome	2020-11-24	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 540 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001251418	SCV001427008	uncertain significance	not specified	2020-07-30	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1618G>A (p.Glu540Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250866 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1618G>A in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV000775176	SCV002705365	uncertain significance	Hereditary cancer-predisposing syndrome	2020-10-08	criteria provided, single submitter	clinical testing	The p.E540K variant (also known as c.1618G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 1618. The glutamic acid at codon 540 is replaced by lysine, an amino acid with similar properties. 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000775176	SCV003851170	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).
Labcorp Genetics (formerly Invitae), Labcorp	RCV003644910	SCV004470729	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-08-28	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 540 of the BRCA1 protein (p.Glu540Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early onset breast cancer (PMID: 33067490). ClinVar contains an entry for this variant (Variation ID: 182133). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. 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.
PreventionGenetics, part of Exact Sciences	RCV004730890	SCV005338895	uncertain significance	BRCA1-related disorder	2024-05-10	no assertion criteria provided	clinical testing	The BRCA1 c.1618G>A variant is predicted to result in the amino acid substitution p.Glu540Lys. This variant was reported in an individual with a history of breast and/or ovarian cancer and was classified as uncertain (Table S3, Patient E10, Abu-Helalah. et al. 2020. PubMed ID: 33067490). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar, this variant has conflicting interpretations ranging from uncertain to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/182133/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.