Submissions for variant NM_000059.4(BRCA2):c.5200G>A (p.Glu1734Lys)

gnomAD frequency: 0.00001  dbSNP: rs786202543

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165399	SCV000216126	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-05	criteria provided, single submitter	clinical testing	The p.E1734K variant (also known as c.5200G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 5200. The glutamic acid at codon 1734 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in multiple individuals with personal and/or family history of breast and/or ovarian cancers (Konstantopoulou I et al. Clin. Genet., 2014 Jan;85:36-42; Singh J et al. Breast Cancer Res. Treat., 2018 Jul;170:189-196; Momozawa Y et al. Nat Commun, 2018 10;9:4083; Zuntini R et al. Front Genet, 2018 Sep;9:378). 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.
Invitae	RCV000205413	SCV000260139	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-11-06	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1734 of the BRCA2 protein (p.Glu1734Lys). This variant is present in population databases (rs786202543, gnomAD 0.005%). This missense change has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 24010542, 29470806, 30254663, 31837001). ClinVar contains an entry for this variant (Variation ID: 185896). 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.
GeneDx	RCV000485722	SCV000572788	uncertain significance	not provided	2022-12-20	criteria provided, single submitter	clinical testing	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 5428G>A; This variant is associated with the following publications: (PMID: 30254663, 24010542, 24807215, 29470806, 30287823, 31837001, 35159047, 31853058, 29884841, 32377563, 33471991, 32467295, 32980694)
Color Diagnostics, LLC DBA Color Health	RCV000165399	SCV000903154	likely benign	Hereditary cancer-predisposing syndrome	2016-09-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804894	SCV002051304	uncertain significance	not specified	2021-12-21	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5200G>A (p.Glu1734Lys) 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 246610 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.5200G>A, has been reported in the literature in individuals affected with breast and/or ovarian cancer (Konstantopoulou_2014, Zuntini_2018, Singh_2018, Guo_2020), however it was also reported in several healthy controls (Momozawa_2018, Dorling_2021, Dong_2021). These reports 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as VUS (n=3), or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Genetic Services Laboratory, University of Chicago	RCV001804894	SCV002068113	uncertain significance	not specified	2020-04-22	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000165399	SCV002533930	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-11	criteria provided, single submitter	curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003153445	SCV003843166	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2022-11-29	criteria provided, single submitter	clinical testing	The BRCA2 c.5200G>A (p.Glu1734Lys) missense change has a maximum subpopulation frequency of 0.0018% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 24010542, 29470806, 30254663), as well as in unaffected individuals (PMID: 30287823, 32467295). This variant is absent in the FLOSSIES database, which contains genetic variants from women older than 70 years of age who have never had cancer (https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with Fanconi anemia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000165399	SCV003847072	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 Medical and Surgical Sciences, University of Bologna	RCV003153445	SCV004228406	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	BP1(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)