ClinVar Miner

Submissions for variant NM_004656.4(BAP1):c.1735G>A (p.Gly579Arg) (rs370004702)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000229762 SCV000288743 likely benign Tumor susceptibility linked to germline BAP1 mutations 2019-12-26 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000229762 SCV000445465 benign Tumor susceptibility linked to germline BAP1 mutations 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx RCV000657094 SCV000617907 uncertain significance not provided 2018-12-19 criteria provided, single submitter clinical testing This variant is denoted BAP1 c.1735G>A at the cDNA level, p.Gly579Arg (G579R) at the protein level, and results in the change of a Glycine to an Arginine (GGG>AGG). This variant has been observed in an individual with endometrial cancer (Lu 2015), at least one individual with features of Cowden or Bannayan-Riley-Ruvalcaba syndrome (Yehia 2018), and in 1/62 healthy East Asian individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in the Bodian study were younger than 50 years old; thus, the unaffected status of this individual may not be significant. BAP1 Gly579Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. 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 BAP1 Gly579Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000573314 SCV000672748 likely benign Hereditary cancer-predisposing syndrome 2018-05-08 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
Color RCV000573314 SCV000902630 likely benign Hereditary cancer-predisposing syndrome 2016-03-18 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000229762 SCV001159711 uncertain significance Tumor susceptibility linked to germline BAP1 mutations 2019-06-24 criteria provided, single submitter clinical testing The BAP1 c.1735G>A; p.Gly579Arg variant (rs370004702) is reported in the literature in an individual with endometrial carcinoma (Lu 2015, supplemental data 12), as well as an individual with Cowden syndrome/Bannayan-Riley-Ruvalcaba syndrome (Yehia 2018, supplemental table 9). This variant is reported in ClinVar (Variation ID: 133666). It is found in the general population with an overall allele frequency of 0.005% (14/282440 alleles) in the Genome Aggregation Database. The glycine at codon 579 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Lu C et al. Patterns and functional implications of rare germline variants across 12 cancer types. Nat Commun. 2015 Dec 22;6:10086. Yehia L et al. Unexpected cancer-predisposition gene variants in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome patients without underlying germline PTEN mutations. PLoS Genet. 2018 Apr 23;14(4):e1007352.
ITMI RCV000120194 SCV000084340 not provided not specified 2013-09-19 no assertion provided reference population

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