Submissions for variant NM_000059.4(BRCA2):c.9372C>A (p.Asn3124Lys)

dbSNP: rs1420566833

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000540722	SCV000635740	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 3124 of the BRCA2 protein (p.Asn3124Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 462524). 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 BRCA2 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 29884841). This variant disrupts the p.Asn3124 amino acid residue in BRCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22678057, 23108138, 24728577, 25085752). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV001775858	SCV002013002	uncertain significance	not provided	2016-03-21	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29884841)
Ambry Genetics	RCV002377052	SCV002688708	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-12	criteria provided, single submitter	clinical testing	The p.N3124K variant (also known as c.9372C>A), located in coding exon 24 of the BRCA2 gene, results from a C to A substitution at nucleotide position 9372. The asparagine at codon 3124 is replaced by lysine, an amino acid with similar properties. This variant had deleterious impact on function in a homology-directed DNA repair (HDR) assay (Hu, C. et al. Clin Cancer Res. 2022 Jun.; Hart SN et al. Genet Med, 2019 01;21:71-80). This amino acid position is highly 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.
Baylor Genetics	RCV004568791	SCV005059168	uncertain significance	Familial cancer of breast	2023-11-30	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001775858	SCV005197331	likely pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
BRCAlab, Lund University	RCV003493632	SCV004243869	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing