ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7975A>G (p.Arg2659Gly) (rs80359026)

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Total submissions: 8
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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 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 RCV000483791 SCV000568488 uncertain significance not specified 2017-05-18 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7975A>G at the cDNA level, p.Arg2659Gly (R2659G) at the protein level, and results in the change of an Arginine to a Glycine (AGA>GGA). This variant, also known as BRCA2 8203A>G using alternate nomenclature, has been reported in at least one individual with a personal and/or family history of breast and/or ovarian cancer (Caux-Moncoutier 2011). This variant has been shown to partially impact splicing, creating a low amount of an alternative transcript with an in-frame deletion of exon 17 in addition to full length transcript (Caux-Moncoutier 2011, Houdayer 2012), and cell based functional studies of BRCA2 Arg2659Gly demonstrated impaired homologous repair activity compared to the wild-type (Guidugli 2013). BRCA2 Arg2659Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Arg2659Gly occurs at a position that is conserved across species and is located in DNA binding domain at a DSS1 contacting residue (Yang 2002). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Arg2659Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000572654 SCV000661425 pathogenic Hereditary cancer-predisposing syndrome 2020-02-12 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, the in silico prediction for this alteration is inconclusive. 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
Invitae RCV001325838 SCV001516845 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 2659 of the BRCA2 protein (p.Arg2659Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals with breast and/or ovarian cancer in the literature (PMID: 21120943, 27553368, 29335924, 30254663). This variant is also known as c.8204G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 38130). Experimental studies have shown that this change results in partial aberrant splicing and production of low amounts of an alternate transcript lacking exon 17 in addition to wild-type transcript (PMID: 22505045, 12624152, 28339459). In vitro functional analysis showed this change results in impaired homologous repair activity compared to wild-type BRCA2 protein (PMID: 15695382, 23108138, 29884841). 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.
Sharing Clinical Reports Project (SCRP) RCV000031712 SCV000054319 uncertain significance Breast-ovarian cancer, familial 2 2009-10-28 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031712 SCV000147231 uncertain significance Breast-ovarian cancer, familial 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 2 no assertion criteria provided clinical testing

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