Submissions for variant NM_007294.4(BRCA1):c.2215A>G (p.Lys739Glu)

gnomAD frequency: 0.00001  dbSNP: rs56329598

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000561453	SCV000665916	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-27	criteria provided, single submitter	clinical testing	The p.K739E variant (also known as c.2215A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 2215. The lysine at codon 739 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is poorly 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587563	SCV000698930	uncertain significance	not provided	2016-05-02	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.2215A>G variant affects a non-conserved nucleotide, resulting in an amino acid change from Lys to Glu. 4/4 in-silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1/121324 control chromosomes at a frequency of 0.0000082, which does not exceed maximal expected frequency of a pathogenic BRCA1 allele (0.0010005). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae	RCV001203880	SCV001375059	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 739 of the BRCA1 protein (p.Lys739Glu). This variant is present in population databases (rs56329598, gnomAD 0.003%). This missense change has been observed in individual(s) with personal and/or family history of breast or ovarian cancer (PMID: 34284872, 36881271). ClinVar contains an entry for this variant (Variation ID: 481479). 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 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.
Genetic Services Laboratory, University of Chicago	RCV001821667	SCV002070150	uncertain significance	not specified	2020-02-17	criteria provided, single submitter	clinical testing	DNA sequence analysis of the BRCA1 gene demonstrated a sequence change, c.2215A>G, in exon 10 that results in an amino acid change, p.Lys739Glu. This sequence change does not appear to have been previously described in patients with BRCA1-related disorders and has been described in the gnomAD database in two individuals (dbSNP rs56329598). The p.Lys739Glu change affects a poorly conserved amino acid residue located in a domain of the BRCA1 protein that is known to be functional. The p.Lys739Glu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to the lack of functional studies, the clinical significance of the p.Lys739Glu change remains unknown at this time.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000561453	SCV003847848	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).
Color Diagnostics, LLC DBA Color Health	RCV000561453	SCV004360280	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-14	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 739 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). 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 been identified in 2/250926 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.