ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8324T>G (p.Met2775Arg) (rs80359073)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129803 SCV000184614 likely benign Hereditary cancer-predisposing syndrome 2017-10-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other data supporting benign classification
Breast Cancer Information Core (BIC) (BRCA2) RCV000113903 SCV000147320 uncertain significance Breast-ovarian cancer, familial 2 2004-03-30 no assertion criteria provided clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769702 SCV000901120 uncertain significance Breast and/or ovarian cancer 2016-08-08 criteria provided, single submitter clinical testing
Color RCV000129803 SCV000906639 likely benign Hereditary cancer-predisposing syndrome 2016-07-05 criteria provided, single submitter clinical testing
GeneDx RCV000587216 SCV000617965 uncertain significance not provided 2018-08-02 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8324T>G at the cDNA level, p.Met2775Arg (M2775R) at the protein level, and results in the change of a Methionine to an Arginine (ATG>AGG). Using alternate nomenclature, this variant would be defined as BRCA2 8552T>G. This variant has been observed in at least two individuals; one with a history of prostate cancer and the other with a history of epithelial ovarian cancer (Cunningham 2014, Maier 2014). BRCA2 Met2775Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in 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 Met2775Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587216 SCV000695143 uncertain significance not provided 2017-06-12 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.8324T>G (p.Met2775Arg) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 118698 control chromosomes. A minigene assay revealed no exon exclusion, albeit the finding was not confirmed by RNA analysis (Thery 2011). The variant has been previously reported in one patient with prostate cancer (Maier 2014) and in at least one patient with ovarian cancer (Cunningham 2014). However, no cosegregation and co-occurrence data were provided. One clinical lab classified this variant as "VUS", another lab classified it as "likely benign", both without evidences for independent evaluation. Another variant at the same residue, p.Met2775Thr has also been reported and classified as VUS by our lab. BIC has reported this variant to co-occur in an ovarian cancer patient along with pathogenic BRCA2 variant c.8754+4A>G, suggesting the benign nature of the variant of interest. Taken together, this variant is classified as VUS-possibly benign, until additional evidence becomes available.
Invitae RCV000045474 SCV000073487 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-01 criteria provided, single submitter clinical testing This sequence change replaces methionine with arginine at codon 2775 of the BRCA2 protein (p.Met2775Arg). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with prostate cancer (PMID: 25111659) as well as an individual affected with ovarian cancer (PMID: 24504028). This variant occurs with a pathogenic variant in BRCA2 in one individual in the Breast Cancer Information Core database (PMID: 10923033). While it is unknown if these variants are on the same or opposite chromosomes, this observation suggests that in that individual, the c.8324T>G variant is not a primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 52547). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). However, an algorithm developed specifically for the BRCA2 gene (PMID: 19043619), suggests that this missense change is likely to be tolerated. The arginine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. 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 RCV000045474 SCV000838873 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing

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