Submissions for variant NM_007294.4(BRCA1):c.4552C>A (p.Gln1518Lys)

dbSNP: rs80356881

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000223155	SCV000276234	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-10	criteria provided, single submitter	clinical testing	The p.Q1518K variant (also known as c.4552C>A), located in coding exon 13 of the BRCA1 gene, results from a C to A substitution at nucleotide position 4552. The glutamine at codon 1518 is replaced by lysine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000227811	SCV000289804	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-12-03	criteria provided, single submitter	clinical testing	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. 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: 232176). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 1518 of the BRCA1 protein (p.Gln1518Lys).
GeneDx	RCV000482259	SCV000566816	uncertain significance	not provided	2017-10-25	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.4552C>A at the cDNA level, p.Gln1518Lys (Q1518K) at the protein level, and results in the change of a Glutamine to a Lysine (CAG>AAG). Using alternate nomenclature, this variant would be defined as BRCA1 4671C>A. This variant has been identified in at least one individual with a personal and/or family history of breast and/or ovarian cancer (Sibille-Hoang 1998). BRCA1 Gln1518Lys was not observed in large population cohorts (Lek 2016). Since Glutamine and Lysine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Gln1518Lys occurs at a position that is not conserved and is located in the SCD domain and in a region known to interact with multiple other proteins (Narod 2004, Clark 2012, Paul 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Gln1518Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000223155	SCV002053717	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-24	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with lysine at codon 1518 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). A functional study has shown that this variant does not impact sensitivity to PARP inhibitors nor homology-directed DNA repair activity (PMID: 32546644). To our knowledge, this variant has not been reported in individuals affected with BRCA1-related disorders 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.