ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8350C>T (p.Arg2784Trp) (rs80359075)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045487 SCV000073500 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 2784 of the BRCA2 protein (p.Arg2784Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs80359075, ExAC <0.01%). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 16683254, 27616075). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). However, in one of those individuals a likely pathogenic allele was also identified in BRCA2, which suggests that this c.8350C>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 38155). Experimental studies have shown that this missense change disrupts BRCA2 homology-directed DNA break repair activity, but it has not been shown to affect centrosome amplification (PMID: 18451181, 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.
Ambry Genetics RCV000131691 SCV000186727 likely pathogenic Hereditary cancer-predisposing syndrome 2018-02-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000392114 SCV000329141 likely pathogenic not provided 2018-11-21 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8350C>T at the cDNA level, p.Arg2784Trp (R2784W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). Using alternate nomenclature, this variant would be defined as BRCA2 8578C>T. This variant has been identified in individuals with a personal and/or family history of breast and/or ovarian cancer (van der Hout 2006, Gomez Garcia 2009, Brandao 2011). While BRCA2 Arg2784Trp did not induce centrosome amplification, this variant displayed reduced homologous recombination repair activity in multiple homology-directed DNA break repair assays, which have been shown to have high sensitivity and specificity for determining pathogenicity of BRCA2 missense variants in the DNA-binding domain (Farrugia 2008, Guidugli 2013, Mesman 2018). In addition, a multifactorial analysis combining in silico and functional data classified this variant as pathogenic (Guidugli 2018). BRCA2 Arg2784Trp was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Arginine and Tryptophan differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Arg2784Trp is located within the DSS1 contacting residues of the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on the currently available evidence, we consider BRCA2 Arg2784Trp to be a likely pathogenic variant.
Color RCV000131691 SCV000911858 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-06 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000392114 SCV001133931 likely pathogenic not provided 2019-01-15 criteria provided, single submitter clinical testing The best available variant frequency is uninformative. Predicted to have a damaging effect on the protein. Located in potentially important domain of the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. Found in at least one symptomatic patient.
Mendelics RCV000031738 SCV001139212 likely pathogenic Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031738 SCV000054345 uncertain significance Breast-ovarian cancer, familial 2 2012-09-25 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031738 SCV000147329 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing

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