Submissions for variant NM_000059.4(BRCA2):c.6024G>C (p.Lys2008Asn)

gnomAD frequency: 0.00005  dbSNP: rs56324666

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129322	SCV000184085	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-26	criteria provided, single submitter	clinical testing	The p.K2008N variant (also known as c.6024G>C), located in coding exon 10 of the BRCA2 gene, results from a G to C substitution at nucleotide position 6024. The lysine at codon 2008 is replaced by asparagine, an amino acid with similar properties. This alteration was detected in a cohort of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). 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.
GeneDx	RCV000590592	SCV000210379	uncertain significance	not provided	2023-07-13	criteria provided, single submitter	clinical testing	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 6252G>C; This variant is associated with the following publications: (PMID: 32377563, 29884841, 31853058, 31911673, 35264596, 36881271)
Invitae	RCV000204438	SCV000260122	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-10	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 2008 of the BRCA2 protein (p.Lys2008Asn). This variant is present in population databases (rs56324666, gnomAD 0.02%). This missense change has been observed in individual(s) with a personal and/or family history of breast cancer (PMID: 35264596, 36881271). ClinVar contains an entry for this variant (Variation ID: 141008). 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%. 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.
Counsyl	RCV000409077	SCV000488258	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-02-09	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590592	SCV000600675	uncertain significance	not provided	2019-08-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001268978	SCV000694927	uncertain significance	not specified	2020-11-25	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6024G>C (p.Lys2008Asn) results in a non-conservative amino acid change located in the RAD51-binding domain (PMID: 22193408) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250716 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.6024G>C in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics	RCV000204438	SCV000838828	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129322	SCV000906124	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-27	criteria provided, single submitter	clinical testing
Mendelics	RCV000409077	SCV001139132	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129322	SCV003850867	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).