Submissions for variant NM_000059.4(BRCA2):c.6058G>A (p.Glu2020Lys)

gnomAD frequency: 0.00004  dbSNP: rs80358842

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129466	SCV000184236	likely benign	Hereditary cancer-predisposing syndrome	2021-05-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
GeneDx	RCV000587558	SCV000210381	uncertain significance	not provided	2023-02-13	criteria provided, single submitter	clinical testing	Published functional studies demonstrate no damaging effect: variant classified as likely normal in a PARP inhibitor assay (Ikegami et al., 2020); 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 6286G>A; This variant is associated with the following publications: (PMID: 11698567, 26689913, 22476429, 31131967, 29470806, 32444794)
Counsyl	RCV000113521	SCV000487869	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2015-12-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000471466	SCV000549600	likely benign	Hereditary breast ovarian cancer syndrome	2024-10-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000160106	SCV000694931	uncertain significance	not specified	2019-11-01	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6058G>A (p.Glu2020Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250910 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6058G>A has been reported in the literature in individuals with a personal or family history of breast/ovarian cancer (Hartmann_2001, Lu_2012, Singh_2018), however, with limited information (i.e. lack of co-occurrence and cosegregation data). These reports therefore do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. A co-occurrence with a pathogenic variant has been reported (BRCA1 c.4206_4207delTA, p.His1402GlnfsX11; UMD), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000129466	SCV000903522	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-14	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 2020 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). A functional study has shown that this variant has no impact on sensitivity to PARP inhibitors (PMID: 32444794). This variant has been reported in individuals affected with breast and/or ovarian cancer, and prostate cancer (PMID: 11698567, 22476429, 29470806, 31214711). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 2/60466 cases and 4/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001098). This variant has been reported in a multifactorial analysis with segregation, tumor pathology, co-occurrence and family history likelihood ratios for pathogenicity of 0.1762, 0.9523, 1.0757 and 0.786, respectively (PMID: 31131967). This variant has been identified in 1/245768 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	RCV000587558	SCV002046522	uncertain significance	not provided	2024-08-23	criteria provided, single submitter	clinical testing	The BRCA2 c.6058G>A (p.Glu2020Lys) variant has been reported in the published literature in individuals affected with and at high risk for breast and/or ovarian cancer (PMIDs: 11698567 (2001), 22476429 (2012), 29470806 (2018), and 33471991 (2021); LOVD3 Shared (https://databases.lovd.nl/shared/)), as well as in an individual affected with glioblastoma multiforme (PMID: 26689913 (2015)). One functional study using a colorectal cancer cell line reports this variant likely does not affect the homology directed repair function of BRCA2 protein, however it is not clear if these results are reproducible in other cell lines (PMID: 32444794 (2020)). The frequency of this variant in the general population, 0.000059 (4/67974 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129466	SCV003850889	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).
All of Us Research Program, National Institutes of Health	RCV000113521	SCV004846689	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 2020 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). A functional study has shown that this variant has no impact on sensitivity to PARP inhibitors (PMID: 32444794). This variant has been reported in individuals affected with breast and/or ovarian cancer, and prostate cancer (PMID: 11698567, 22476429, 29470806, 31214711). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 2/60466 cases and 4/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001098). This variant has been reported in a multifactorial analysis with segregation, tumor pathology, co-occurrence and family history likelihood ratios for pathogenicity of 0.1762, 0.9523, 1.0757 and 0.786, respectively (PMID: 31131967). This variant has been identified in 1/245768 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.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113521	SCV000146756	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2000-06-12	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000113521	SCV000189311	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2009-08-28	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354010	SCV000592024	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Glu2020Lys variant was identified in 1 of 352 proband chromosomes (frequency: 0.003) from individuals or families with breast cancer (Hartmann 2001). The variant was also identified in dbSNP (ID: rs80358842) “With uncertain significance, untested allele”, Exome Aggregation Consortium (ExAC) database, COSMIC, the ClinVar database (classified as an uncertain significance variant by the Sharing Clinical Reports Project, derived from Myriad reports; BIC, Ambry Genetics and GeneDx), the BIC database (2X with unknown clinical importance), and UMD (4X as an unclassified variant). In UMD the variant was identified with a co-occurring pathogenic BRCA1 variant (c.4206_4207delTA (p.His1402GlnfsX11)), increasing the likelihood that the p.Glu2020Lys variant does not have clinical significance. This variant was identified in the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 1 of 66330 chromosomes (1 individual) from a population of European (Non-Finnish) individuals, although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease.The p.Glu2020 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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 unknown significance.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000587558	SCV001960040	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000587558	SCV001971273	likely benign	not provided		no assertion criteria provided	clinical testing