ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8524C>T (p.Arg2842Cys) (rs80359104)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165225 SCV000215939 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other strong data supporting pathogenic classification
Breast Cancer Information Core (BIC) (BRCA2) RCV000077443 SCV000147390 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing
Cancer Variant Interpretation Group UK,Institute of Cancer Research, London RCV000045544 SCV000897864 pathogenic Hereditary breast and ovarian cancer syndrome 2018-10-31 criteria provided, single submitter clinical testing Data used in classification: This variant has been seen in trans with an established pathogenic variant in BRCA2 in a UK case of Fanconi D1 (chromosome breakage studies abnormal, BRCA2 ubiquitination function intermediate). Reduced level of BRCA2 protein on Western blot giving gene-phenotype specificity (PP4). BRCA2 was fully screened in this case (PM3). The variant is deleterious on the HR assay described by Guidugli et al (Couch laboratory), p=0.99 in 2013 and p=0.987 (2018) (PS3). Delirious on AlignGVGD, SIFT, Polyphen (PP3). Located in DNA binding domain (PM1_sup). In the GNOMAD NFE population of 63,369 individuals, the frequency of this variant is 1 (PM2-sup). Additional Information (not included in classification): There are additional reports of this variant in [ClinVar (5) , BIC (1), UMD (5) and BRCA2 LOVD (1)]. Reported several times in ENIGMA in HBOC families (verbal report). Comment: We have classified this as pathogenic but of intermediate penetrance based on (i) lack of cancer in index Fanconi case at age 10 (ii) Couch assay of 0.987 (all positive controls were p>0.99) (iii) BRCA2 ubiquitination function intermediate (iii) lack of family history in large pedigree for UK Fanconi case.
Color RCV000165225 SCV000911453 likely benign Hereditary cancer-predisposing syndrome 2017-10-25 criteria provided, single submitter clinical testing
Department of Pathology and Molecular Medicine,Queen's University RCV000212277 SCV000588119 uncertain significance not specified 2017-04-20 criteria provided, single submitter clinical testing
GeneDx RCV000656805 SCV000210475 uncertain significance not provided 2018-08-03 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8524C>T at the cDNA level, p.Arg2842Cys (R2842C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant was absent from 2575 breast cancer cases, but was present in 1/2809 controls in a case-control study (Wen 2018). Functional studies demonstrate that this variant impacts BRCA2 with respect to homology directed repair, but exhibits normal sensitivity to DNA damaging agents and does not impact splicing (Guidugli 2013, de Garibay 2014, Guidugli 2018, Mesman 2018). BRCA2 Arg2842Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in 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 currently available evidence, it is unclear whether BRCA2 Arg2842Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000212277 SCV000916900 uncertain significance not specified 2018-06-05 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.8524C>T (p.Arg2842Cys) results in a non-conservative amino acid change located in the Tower domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.4e-05 in 282302 control chromosomes. c.8524C>T has been reported to co-occur with other pathogenic variant(s) (BRCA1 c.135-1G>T, BIC database), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. Guidugli_2012 showed variant with defective HDR activity with a 99% probability of deleteriousness and was listed among 5 VUS that displayed activity that was marginally above the activity of known pathogenic mutations. de Garibay_2014 showed variant does not affect splicing. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic
Invitae RCV000045544 SCV000073557 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 2842 of the BRCA2 protein (p.Arg2842Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant is reported in the Breast Cancer Information Core database to co-occur with a pathogenic BRCA1 variant, which suggests that this c.8524C>T variant was not the primary cause of disease (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 52610). In a large scale functional study of BRCA2 variants, this missense change was found to show an intermediate activity in a homologous-directed repair (HDR) assay (PMID: 24323938). 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.
Mendelics RCV000045544 SCV000838879 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212277 SCV000600811 uncertain significance not specified 2016-06-04 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077443 SCV000109241 likely benign Breast-ovarian cancer, familial 2 2011-02-09 no assertion criteria provided clinical testing

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