Submissions for variant NM_000059.4(BRCA2):c.2389A>G (p.Lys797Glu)

gnomAD frequency: 0.00002  dbSNP: rs587782737

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000168301	SCV000218982	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 797 of the BRCA2 protein (p.Lys797Glu). This variant is present in population databases (rs587782737, 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: 188307). 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.
Department of Pathology and Molecular Medicine, Queen's University	RCV000496950	SCV000588084	uncertain significance	not specified	2017-04-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000574060	SCV000668566	likely benign	Hereditary cancer-predisposing syndrome	2018-10-29	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000574060	SCV000911753	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 797 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BRCA2-related disorders in the literature. This variant has been identified in 1/31410 chromosomes 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985478	SCV001133711	uncertain significance	not provided	2019-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000985478	SCV001788502	uncertain significance	not provided	2023-04-04	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer (Alvarez et al., 2017); Also known as 2617A>G; This variant is associated with the following publications: (PMID: 31853058, 29884841, 32377563, 29088781)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496950	SCV002041854	uncertain significance	not specified	2021-11-17	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000985478	SCV002048495	uncertain significance	not provided	2020-10-15	criteria provided, single submitter	clinical testing	The BRCA2 c.2389A>G; p.Lys797Glu variant (rs587782737), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 188307). This variant is found on a single chromosome (1/31410 alleles) in the Genome Aggregation Database. The lysine at codon 797 is moderately conserved, and computational analyses predict that this variant is neutral (REVEL: 0.122). However, due to limited information, the clinical significance of the p.Lys797Glu variant is uncertain at this time.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000574060	SCV003848279	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000985478	SCV001554169	uncertain significance	not provided		no assertion criteria provided	clinical testing	The BRCA2 p.Lys797Glu variant was not identified in the literature nor was it identified in the LOVD 3.0 or UMD LSDB databases. The variant was identified in dSNP (rs587782737) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Invitae, and COGR; as likely benign by Ambry Genetics). The variant was identified in control databases in 1 of 30976 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the Other population in 1 of 982 chromosomes (freq: 0.001), while the variant was not observed in the European, African, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Lys797 residue is not conserved in mammals, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.