Submissions for variant NM_000059.4(BRCA2):c.5663A>G (p.Lys1888Arg)

gnomAD frequency: 0.00001  dbSNP: rs80358791

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044713	SCV000072726	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 1888 of the BRCA2 protein (p.Lys1888Arg). This variant is present in population databases (rs80358791, gnomAD 0.003%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 18256760, 32380732). ClinVar contains an entry for this variant (Variation ID: 51903). 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	RCV000131719	SCV000186758	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-08	criteria provided, single submitter	clinical testing	The p.K1888R variant (also known as c.5663A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 5663. The lysine at codon 1888 is replaced by arginine, an amino acid with highly similar properties. This alteration has been identified in a study of 74 Russian individuals diagnosed with ovarian cancer (Smirnova TY et al. Bull. Exp. Biol. Med., 2007 Jul;144:83-5). Additonally, this alteration was identified in an individual diagnosed with breast cancer (Fanale D et al. Front Oncol, 2021 Jun;11:682445). This variant was also reported in 1/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med 2021 02;384:428-439). 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. Based on the available evidence, the clinical significance of this variant remains unclear.
GeneDx	RCV000216952	SCV000278864	uncertain significance	not provided	2024-08-16	criteria provided, single submitter	clinical testing	Observed in individuals with breast or ovarian cancer (PMID: 18256760, 34178674); In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5891 A>G; This variant is associated with the following publications: (PMID: 18256760, 31131967, 34178674, 10923033)
Color Diagnostics, LLC DBA Color Health	RCV000131719	SCV000903262	likely benign	Hereditary cancer-predisposing syndrome	2016-04-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779946	SCV000916891	uncertain significance	not specified	2024-11-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5663A>G (p.Lys1888Arg) results in a conservative amino acid change in the encoded protein sequence. Five 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 249646 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5663A>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Smirnova_2007, Incorvaia_2020, Fanale_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34178674, 32380732, 18256760). ClinVar contains an entry for this variant (Variation ID: 51903). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000216952	SCV001133835	uncertain significance	not provided	2021-04-12	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000779946	SCV002071167	uncertain significance	not specified	2019-09-12	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131719	SCV002536160	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-13	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000779946	SCV002550351	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000131719	SCV003848994	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).
Mayo Clinic Laboratories, Mayo Clinic	RCV000216952	SCV004226423	uncertain significance	not provided	2022-09-23	criteria provided, single submitter	clinical testing	BP4, PM2
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113457	SCV000146661	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-06-20	no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735571	SCV000863709	uncertain significance	Breast and/or ovarian cancer	2016-05-18	no assertion criteria provided	clinical testing