Submissions for variant NM_000059.4(BRCA2):c.5125G>T (p.Asp1709Tyr)

dbSNP: rs398122792

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206087	SCV000259620	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-11-21	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 1709 of the BRCA2 protein (p.Asp1709Tyr). This variant is present in population databases (rs398122792, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 31851867, 34196900, 34413315). ClinVar contains an entry for this variant (Variation ID: 91833). 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	RCV000213126	SCV000278072	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-04	criteria provided, single submitter	clinical testing	The p.D1709Y variant (also known as c.5125G>T), located in coding exon 10 of the BRCA2 gene, results from a G to T substitution at nucleotide position 5125. The aspartic acid at codon 1709 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been identified in an individual at increased risk for hereditary breast and/or ovarian cancer (Peker Eyübolu et al. OMICS, 2020 Jan;24:5-15). This amino acid position is poorly 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002228188	SCV000494384	uncertain significance	not specified	2022-04-17	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5125G>T (p.Asp1709Tyr) results in a non-conservative amino acid change located in the BRCA2 repeat region (IPR002093) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-06 in 226648 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5125G>T has been reported in the literature as a VUS in settings of BRCA analysis (example, Herzog_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. Five 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.
Counsyl	RCV000077741	SCV000786427	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-04-30	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758905	SCV000887839	uncertain significance	not provided	2021-07-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000213126	SCV001352423	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-11	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with tyrosine at codon 1709 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 been reported in two individuals with a personal or family history of cancer and in one unaffected individual (PMID: 31851867, 33471991; Leiden Open Variation Database DB-ID BRCA2_008302, 34413315). This variant has been identified in 1/226648 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000213126	SCV003847011	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).
GeneDx	RCV000758905	SCV003931108	uncertain significance	not provided	2022-12-07	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 5353G>T; Observed in individuals with a personal and/or family history of breast and ovarian cancer (Bahsi et al., 2019; Peker Eybolu et al., 2020; Herzog et al., 2021); This variant is associated with the following publications: (PMID: 31851867, Bahsi2019[article], 29884841, 33471991, 34413315, 22923510, 32377563)
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000077741	SCV003932736	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-06	criteria provided, single submitter	clinical testing	A variant on uncertain significance was detected in the BRCA2 gene (c.5125G>T). The p.Asp1709Tyr variant located in coding exon 11 of the BRCA2 gene, results from a G to T substitution at nucleotide position 5125. The Aspartate at codon 1709 is replaced by Tyrosine , This amino acid position is not conserved (PhyloP=-0.65). This variant not present in our local database and found in population databases (rs398122792, gnomAD 0.004%). .This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 22923510, 31851867, 34413315) . Pathogenic computational verdict based on 4 pathogenic predictions from tools ( BLOSUM , PROVEAN , MutationTaster and SIFT) vs 8 benign predictions from PolyPhen, DANN, EIGEN, FATHMM, M-CAP, MutPred , PrimateAI, MVP and LRT . ClinVar has an entry (91833) submitted from 7 diagnostic labs as uncertain significance . Since supporting evidence is limited at this time, this variant is classified as of uncertain significance.
All of Us Research Program, National Institutes of Health	RCV000077741	SCV004845771	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-01	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000758905	SCV005199790	uncertain significance	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005007991	SCV005633927	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3; Familial prostate cancer	2024-05-05	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077741	SCV000109544	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-04-05	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000077741	SCV004243653	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing