ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8092G>A (p.Ala2698Thr) (rs80359052)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000755863 SCV000883489 uncertain significance not provided 2017-07-19 criteria provided, single submitter clinical testing The BRCA2 c.8092G>A;p.Ala2698Thr variant has been described in the medical literature in an individual with breast cancer and a family history of cancer (Manguoglu 2010). The variant is listed in the ClinVar database (Variation ID: 38138), the dbSNP variant database (rs80359052), and the Genome Aggregation Database with an allele frequency of 0.004331 percent (12/277058 alleles). The amino acid at this position is weakly conserved across species, with several mammalian species with threonine at this position, and computational algorithms (AlignGVGD, SIFT, MutationTaster) predict this variant is tolerated. Considering available information, the clinical significance cannot be determined with certainty. References: Manguoglu E et al. Germline mutations of BRCA1 and BRCA2 genes in Turkish breast, ovarian, and prostate cancer patients. Cancer Genet Cytogenet. 2010 Dec;203(2):230-7.
Ambry Genetics RCV000129982 SCV000184806 likely benign Hereditary cancer-predisposing syndrome 2018-04-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other strong data supporting benign classification
Breast Cancer Information Core (BIC) (BRCA2) RCV000031720 SCV000147272 uncertain significance Breast-ovarian cancer, familial 2 1998-11-30 no assertion criteria provided clinical testing
Color RCV000129982 SCV000905495 likely benign Hereditary cancer-predisposing syndrome 2015-09-23 criteria provided, single submitter clinical testing
Counsyl RCV000031720 SCV000487854 uncertain significance Breast-ovarian cancer, familial 2 2015-11-23 criteria provided, single submitter clinical testing
GeneDx RCV000074554 SCV000108639 likely benign not specified 2017-11-03 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000074554 SCV000918820 uncertain significance not specified 2018-02-05 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.8092G>A (p.Ala2698Thr) results in a non-conservative amino acid change located in the BRCA2, OB1 domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-05 in 277058 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (4.3e-05 vs 0.00075), allowing no conclusion about variant significance. c.8092G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer without strong evidence for causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four 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 uncertain significance.
Invitae RCV000531554 SCV000635637 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-04-13 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 2698 of the BRCA2 protein (p.Ala2698Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs80359052, ExAC 0.02%). This variant has been reported in an individual affected with breast cancer in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 38138). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The threonine amino acid residue is 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 RCV000531554 SCV000838867 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000755863 SCV000889152 uncertain significance not provided 2017-11-14 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031720 SCV000054327 uncertain significance Breast-ovarian cancer, familial 2 2007-03-13 no assertion criteria provided clinical testing

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