Submissions for variant NM_007294.4(BRCA1):c.919A>G (p.Lys307Glu)

gnomAD frequency: 0.00001  dbSNP: rs1216516227

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000572449	SCV000668420	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-07	criteria provided, single submitter	clinical testing	The p.K307E variant (also known as c.919A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 919. The lysine at codon 307 is replaced by glutamic acid, an amino acid with similar properties. This alteration was detected in 10/92 breast and/or ovarian cancer families from mainland China and was noted to be the most common variant in BRCA1 found in this cohort (Kim YC et al. Oncotarget. 2016 Feb 23;7(8):9600-12). 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 alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000572449	SCV000683376	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-18	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 307 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 been reported in individuals affected with familial breast and/or ovarian cancer (PMID: 26848529). In a large breast cancer case-control study, this variant has been observed in 0/60466 cases and 2/53461 unaffected controls (PMID: 33471991). This variant has been identified in 2/251354 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	RCV000691850	SCV000819646	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-08-07	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 307 of the BRCA1 protein (p.Lys307Glu). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 26848529, 30702160). ClinVar contains an entry for this variant (Variation ID: 482907). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758853	SCV000887740	uncertain significance	not provided	2018-04-27	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000572449	SCV003846291	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).