Submissions for variant NM_007294.4(BRCA1):c.1012A>G (p.Lys338Glu)

dbSNP: rs397508826

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000465932	SCV000549401	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-08-15	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 338 of the BRCA1 protein (p.Lys338Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 35957908). ClinVar contains an entry for this variant (Variation ID: 409360). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586428	SCV000698826	uncertain significance	not provided	2016-08-08	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.1012A>G (p.Lys338Glu) variant causes a missense change involving a non-conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP), nor has it been, to our knowledge, reported in affected individuals via publications and/or reputable databases/clinical laboratories. An internal LCA reports the variant to co-occur with a pathogenic BRCA2 variant, c.5073dupA (p.Trp1692fsX3 - classified as pathogenic by LCA). Therefore, until additional information becomes available, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000586428	SCV002009479	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV003157520	SCV003846232	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).
GeneDx	RCV000586428	SCV005078010	uncertain significance	not provided	2023-12-12	criteria provided, single submitter	clinical testing	Observed in a patient with breast cancer (PMID: 35957908); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 1131A>G; This variant is associated with the following publications: (PMID: 29884841, 32377563, 20215511, 11521194, 9582019, 9926942, 15343273, 35957908)
Ambry Genetics	RCV003157520	SCV005547450	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-04	criteria provided, single submitter	clinical testing	The p.K338E variant (also known as c.1012A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 1012. The lysine at codon 338 is replaced by glutamic acid, 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. Based on the available evidence, the clinical significance of this variant remains unclear.