Submissions for variant NM_000059.4(BRCA2):c.7975A>G (p.Arg2659Gly)

dbSNP: rs80359026

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031712	SCV001161662	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.999975
GeneDx	RCV001268917	SCV000568488	pathogenic	not provided	2023-08-21	criteria provided, single submitter	clinical testing	Observed in individuals with a personal and/or family history consistent with Hereditary Breast and Ovarian Cancer, and has been found to segregate with disease in multiple affected individuals (Pinto et al., 2016; Apessos et al., 2018; Jakimovska et al., 2018; Zuntini et al., 2018; Li et al., 2019; Parsons et al., 2019; Barbosa et al., 2020; Huang et al., 2020; Gao et al., 2020; Caputo et al., 2021); Protein-based functional studies demonstrate a damaging effect: impaired homology-directed repair activity and sensitivity to PARP inhibitors (Guidugli et al., 2018; Hart et al., 2019; Ikegami et al., 2020; Iversen et al., 2022); Splicing functional studies are inconclusive demonstrating 3% - 26% abnormal transcript (Davy et al., 2017; Fraile-Bethencourt et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Also known as 8203A>G; This variant is associated with the following publications: (PMID: 23108138, 24323938, 25348012, 21523855, 19043619, 21120943, 28339459, 22505045, 27553368, 27060066, 28905878, 29335924, 29752822, 29310832, 32444794, 31131967, 30254663, 29394989, 33008098, 33194720, 29884841, 35665744, 12228710, 31825140, 34597585)
Ambry Genetics	RCV000572654	SCV000661425	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-16	criteria provided, single submitter	clinical testing	The p.R2659G pathogenic mutation (also known as c.7975A>G), located in coding exon 16 of the BRCA2 gene, results from an A to G substitution at nucleotide position 7975. The arginine at codon 2659 is replaced by glycine, an amino acid with dissimilar properties. This alteration, along with close-match alteration BRCA2 c.7976G>A (p.R2659K) are located near a canonical splice donor site and result in in-frame, exon 16 skipping (Fraile-Bethencourt E et al. PLoS Genet. 2017 Mar;13:e1006691; Caux-Moncoutier V et al. Hum. Mutat. 2011 Mar;32:325-34; Houdayer C et al. Hum. Mutat. 2012 Aug;33:1228-38; Hofmann W et al. J Med Genet. 2003 Mar;40(3):e23). Both of these alterations are also non-functional in protein-based homology-directed DNA repair (HDR) assay (Guidugli L et al. Am. J. Hum. Genet. 2018 Jan; Wu K et al. Cancer Res. 2005 Jan;65:417-26; Guidugli L et al. Cancer Res. 2013 Jan;73:265-75). This alteration is considered pathogenic by multifactorial analysis that considers cosegregation, tumor pathology, co-occurrence with pathogenic mutation, family history and case-control data. Of note, the co-segregation likelihood ratio was particularly strong for this variant in this study (Parsons MT et al. Hum. Mutat., 2019 09;40:1557-1578). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Internal structural analysis suggests the arginine at codon 2659 closely interacts with other amino acids where other pathogenic substitutions have been identified. Further, the presence of a glycine at codon 2659 is likely to disrupt DNA binding (Ambry internal data). Based on the majority of available evidence to date, this alteration is interpreted as a disease-causing mutation.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001268917	SCV001448171	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001325838	SCV001516845	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 2659 of the BRCA2 protein (p.Arg2659Gly). RNA analysis indicates that this missense change induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 21120943, 27553368, 29335924, 29752822, 30254663). This variant is also known as 8204G>A. ClinVar contains an entry for this variant (Variation ID: 38130). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 31131967). Experimental studies have shown that this missense change affects BRCA2 function (PMID: 15695382, 23108138, 29884841). Studies have shown that this missense change results in skipping of exon 17, but is expected to preserve the integrity of the reading-frame (PMID: 12624152, 22505045, 28339459). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001268917	SCV002049730	likely pathogenic	not provided	2021-01-20	criteria provided, single submitter	clinical testing	The BRCA2 c.7975A>G; p.Arg2659Gly variant (rs80359026) is reported in the literature in several individuals affected with suspected hereditary breast and/or ovarian cancer syndrome (Apessos 2018, Caux-Moncoutier 2011, Li 2019). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Multifactorial likelihood analyses, incorporating personal and family history of cancer, co-occurrence with pathogenic variants, and co-segregation with disease, suggest the p.Arg2659Gly variant is highly likely to be disease-causing (Parsons 2019). The arginine at codon 2659 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.871). Consistent with these predictions, functional assays of homology-directed repair suggest the variant protein has significantly reduced activity (Guidugli 2013). Further, this variant occurs in the penultimate nucleotide of exon 17, and splicing analyses suggest a low level of exon skipping in cells expressing the variant (Fraile-Bethencourt 2017, Houdayer 2019). Based on available information, this variant is considered to be likely pathogenic. References: Apessos et al. Comprehensive BRCA mutation analysis in the Greek population. Experience from a single clinical diagnostic center. Cancer Genet. 2018 Jan;220:1-12. Caux-Moncoutier V et al. EMMA, a cost- and time-effective diagnostic method for simultaneous detection of point mutations and large-scale genomic rearrangements: application to BRCA1 and BRCA2 in 1,525 patients. Hum Mutat. 2011 Mar;32(3):325-34. Fraile-Bethencourt et al. Functional classification of DNA variants by hybrid minigenes: Identification of 30 spliceogenic variants of BRCA2 exons 17 and 18. PLoS Genet. 2017 Mar 24;13(3):e1006691. Guidugli L et al. A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity. Cancer Res. 2013 Jan 1;73(1):265-75. Houdayer C et al. Guidelines for splicing analysis in molecular diagnosis derived from a set of 327 combined in silico/in vitro studies on BRCA1 and BRCA2 variants. Hum Mutat. 2012 Aug;33(8):1228-38. Li et al. Germline mutations in 40 cancer susceptibility genes among Chinese patients with high hereditary risk breast cancer. Int J Cancer. 2019 Jan 15;144(2):281-289. Parsons MT et al. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification. Hum Mutat. 2019 Sep;40(9):1557-1578.
Mendelics	RCV002247404	SCV002518605	pathogenic	Familial cancer of breast	2022-05-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002247404	SCV004212786	pathogenic	Familial cancer of breast	2022-06-07	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031712	SCV000054319	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2009-10-28	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031712	SCV000147231	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	1998-07-10	no assertion criteria provided	clinical testing
Laboratoire de Biologie et Génétique du Cancer, Centre François Baclesse	RCV000031712	SCV000538193	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000031712	SCV004243790	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing