ClinVar Miner

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

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000572654 SCV000661425 likely pathogenic Hereditary cancer-predisposing syndrome 2018-01-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Well-characterized mutation at same position,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Structural Evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000031712 SCV000147231 uncertain significance Breast-ovarian cancer, familial 2 1998-07-10 no assertion criteria provided clinical testing
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.
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
Sharing Clinical Reports Project (SCRP) RCV000031712 SCV000054319 uncertain significance Breast-ovarian cancer, familial 2 2009-10-28 no assertion criteria provided clinical testing

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