Submissions for variant NM_000059.4(BRCA2):c.3540G>C (p.Lys1180Asn)

dbSNP: rs864622363

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206612	SCV000260309	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 1180 of the BRCA2 protein (p.Lys1180Asn). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with ovarian and/or breast cancer (PMID: 30093976, 32101877, 35918668). ClinVar contains an entry for this variant (Variation ID: 220061). 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 BRCA2 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.
Ambry Genetics	RCV000220199	SCV000277301	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-03	criteria provided, single submitter	clinical testing	The p.K1180N variant (also known as c.3540G>C), located in coding exon 10 of the BRCA2 gene, results from a G to C substitution at nucleotide position 3540. The lysine at codon 1180 is replaced by asparagine, an amino acid with similar properties. This alteration has been reported as a variant of unknown significance in an individual with a personal history of ovarian cancer from a cohort of 1191 cancer index patients who underwent clinical evaluation and testing with multigene panels (Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660). In another study, this alteration was detected in a patient diagnosed with breast cancer at age 51 (Wu H et al. Hum Hered, 2019 Feb;84:160-169). This amino acid position is not 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.
Color Diagnostics, LLC DBA Color Health	RCV000220199	SCV000688814	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-14	criteria provided, single submitter	clinical testing
GeneDx	RCV001560226	SCV001782591	uncertain significance	not provided	2022-12-29	criteria provided, single submitter	clinical testing	Observed in individuals with breast or ovarian cancer (Chan et al., 2018; Wu et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 3768G>C; This variant is associated with the following publications: (PMID: 32101877, 30093976, 29884841, 32377563)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000220199	SCV003846690	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).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001560226	SCV004219592	uncertain significance	not provided	2023-06-18	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMID: 32101877 (2019), 35918668 (2022)) and ovarian cancer (PMID: 30093976 (2018)). In a large-scale breast cancer association study, the variant was observed in an individual with breast cancer as well as in an unaffected individual (PMID: 33471991 (2021)). The frequency of this variant in the general population, 0.000004 (1/250916 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003491953	SCV004240305	uncertain significance	Breast and/or ovarian cancer	2023-05-05	criteria provided, single submitter	clinical testing
Center for Precision Medicine, Meizhou People's Hospital	RCV002250596	SCV002520784	uncertain significance	Familial cancer of breast		no assertion criteria provided	curation