ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1993A>G (p.Thr665Ala) (rs144192844)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130109 SCV000184939 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000586597 SCV000210279 uncertain significance not provided 2018-12-11 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.1993A>G at the cDNA level, p.Thr665Ala (T665A) at the protein level, and results in the change of a Threonine to an Alanine (ACA>GCA). Using alternate nomenclature, this variant would be defined as BRCA2 2221A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Thr665Ala 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 a deleterious effect. Based on currently available evidence, it is unclear whether BRCA2 Thr665Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000586597 SCV000225157 uncertain significance not provided 2015-03-17 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000239179 SCV000296496 uncertain significance Breast-ovarian cancer, familial 2 2016-06-10 criteria provided, single submitter clinical testing
Counsyl RCV000239179 SCV000488922 uncertain significance Breast-ovarian cancer, familial 2 2016-07-19 criteria provided, single submitter clinical testing
Invitae RCV000466395 SCV000549527 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-21 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 665 of the BRCA2 protein (p.Thr665Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs144192844, ExAC 0.02%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 141539). 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 alanine 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 and their clinical significance is uncertain. 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.
Integrated Genetics/Laboratory Corporation of America RCV000586597 SCV000694587 uncertain significance not provided 2016-06-30 criteria provided, single submitter clinical testing Variant summary: The c.1993A>G (p.Thr665Ala) in BRCA2 gene is a missense change that involves a non-conserved nucleotide and 3/5 in silico tools predict deleterious outcome. The variant is present in the control population dataset of ExAC at frequency of 0.000016 (2/119204 chrs tested). The observed frequency does not exceed the maximum expected allele frequency for a pathogenic variant of 0.00075, suggesting that it is not a common polymorphism. The variant has not, to our knowledge, been reported in affected individuals via published reports. The variant of interest has been reported as VUS by reputable databases/clinical laboratories. Taking together, the variant was classified as VUS until more information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586597 SCV000888996 uncertain significance not provided 2018-04-13 criteria provided, single submitter clinical testing
Color RCV000130109 SCV000906499 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-25 criteria provided, single submitter clinical testing

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