ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8515T>C (p.Tyr2839His) (rs758884639)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000167960 SCV000218608 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-08-22 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 2839 of the BRCA2 protein (p.Tyr2839His). The tyrosine residue is moderately conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is present in population databases (rs758884639, ExAC 0.01%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 188108). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx RCV000586024 SCV000569757 uncertain significance not provided 2017-07-07 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8515T>C at the cDNA level, p.Tyr2839His (Y2839H) at the protein level, and results in the change of a Tyrosine to a Histidine (TAC>CAC). Using alternate nomenclature, this variant would be defined as BRCA2 8743T>C. This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in a small cell lung tumor (Jiang 2016). BRCA2 Tyr2839His was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Tyrosine and Histidine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Tyr2839His occurs at a position that is not conserved and is located in the DNA binding domain (Yang 2002). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Tyr2839His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000580149 SCV000683977 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586024 SCV000695162 uncertain significance not provided 2017-02-27 criteria provided, single submitter clinical testing Variant summary: The c.8515T>C (p.Tyr2839His) in BRCA2 gene is a missense change that involves a mildly conserved nucleotide and 4/5 in silico tools predict deleterious outcome. The variant of interest is located outside of any known functional domain or repeats, however no studies determining the functional impact of this variant have been conducted and published at the time of evaluation. The variant is present in the large control population dataset of ExAC at a frequency 1.649e-05 (2/121308 chrs tested), exclusively in individuals of South Asian descent (0.0001212; 2/ 16508) which does not exceed the maximal expected frequency of a pathogenic allele (0.00075) in this gene. The variant has not, to our knowledge, been reported in affected individuals via published reports and has been cited by one reputable clinical lab as a VUS. Taking together, the variant was classified as VUS.

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