Submissions for variant NM_000059.4(BRCA2):c.1564G>C (p.Gly522Arg)

gnomAD frequency: 0.00003  dbSNP: rs80358442

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000043829	SCV000071842	likely benign	Hereditary breast ovarian cancer syndrome	2025-02-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000034431	SCV000210273	likely benign	not provided	2019-05-02	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 22703879, 24916970, 27974047, 25348012, 22476429, 30212499, 28726806)
Ambry Genetics	RCV000165147	SCV000215858	likely benign	Hereditary cancer-predisposing syndrome	2019-02-09	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000200975	SCV000694545	likely benign	not specified	2022-03-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1564G>C (p.Gly522Arg) results in a non-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 allele was found at a frequency of 1.7e-05 in 239116 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1564G>C has been reported in the literature in a proband from high-risk breast and/or ovarian cancer family that did not carry BRCA1 or BRCA2 mutations (Lu_2012), among variants of unknown significance in a Portuguese breast/ovarian cancer family (Peixoto_2014), and among secondary variants identified in a study of Individuals undergoing Exome Sequencing (Johnston_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least two co-occurrences with other pathogenic variant(s) have been reported [BRCA1 c.5136G>A, p.Trp1712Ter (BIC database); BRCA1 c.4258C>T, p.Gln1420Ter (UMD database)], providing supporting evidence for a benign role. No conclusive experimental evidence reporting an impact on protein function has been ascertained. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=3, VUS, n=5). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl	RCV000031327	SCV000785157	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-05-16	criteria provided, single submitter	clinical testing
Mendelics	RCV000043829	SCV000838761	benign	Hereditary breast ovarian cancer syndrome	2023-08-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165147	SCV000902872	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-09	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 522 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 detected in one individual affected with breast cancer (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_002081) and in two suspected hereditary breast and ovarian cancer families (PMID: 22476429, 24916970). This variant has been identified in 4/239116 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	RCV000034431	SCV002046292	likely benign	not provided	2023-09-19	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000165147	SCV003851488	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	RCV004803002	SCV004846931	uncertain significance	BRCA2-related cancer predisposition	2024-06-09	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 522 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 detected in one individual affected with breast cancer (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_002081) and in two suspected hereditary breast and ovarian cancer families (PMID: 22476429, 24916970). This variant has been identified in 4/239116 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.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034431	SCV000043198	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Sharing Clinical Reports Project (SCRP)	RCV000031327	SCV000053932	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2010-10-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031327	SCV000145889	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353896	SCV000591753	uncertain significance	Endometrial carcinoma		no assertion criteria provided	clinical testing	The p.Gly522Arg variant was not identified in the literature but has been reported in the dbSNP (rs80358442), Exome Server Project, UMD (1x as an unknown variant) and BIC (7x with unknown clinical importance) databases. This residue is not conserved in mammals, increasing the likelihood this variant may not have clinical significance. Computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. In summary, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000043829	SCV002506604	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-01-24	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732558	SCV005362708	uncertain significance	BRCA2-related disorder	2024-09-28	no assertion criteria provided	clinical testing	The BRCA2 c.1564G>C variant is predicted to result in the amino acid substitution p.Gly522Arg. This variant has been reported in an individual from a cohort selected for a range of atherosclerosis phenotypes, but not for a personal or family history of cancer (Table S1, Johnston et al. 2012. PubMed ID: 22703879). It was also identified in an individual with breast and/or ovarian cancer and was classified as uncertain (Table 2, Peixoto et al. 2015. PubMed ID: 24916970). This variant is reported in 0.0064% of alleles in individuals of Latino descent in gnomAD and has conflicting interpretations in ClinVar including uncertain (3), likely benign (6), and benign (1) (https://www.ncbi.nlm.nih.gov/clinvar/variation/37746/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.