ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.694T>C (p.Tyr232His) (rs398122572)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129345 SCV000184109 uncertain significance Hereditary cancer-predisposing syndrome 2016-11-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence,In silico models in agreement (benign)
Color RCV000129345 SCV000903260 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-24 criteria provided, single submitter clinical testing
GeneDx RCV000590532 SCV000210252 uncertain significance not provided 2018-02-07 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.694T>C at the cDNA level, p.Tyr232His (Y232H) at the protein level, and results in the change of a Tyrosine to a Histidine (TAT>CAT). Using alternate nomenclature, this variant would be defined as BRCA2 922T>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Tyr232His 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 BRCA2 Tyr232His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000590532 SCV000695013 uncertain significance not provided 2016-09-15 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.694T>C (p.Tyr232His) variant involves the alteration of a non-conserved nucleotide. Tyr232 is not conserved across species and is not located in a known functional domain; 4/5 in silico tools predict a benign outcome for this variant. This variant was found in 1/104314 control chromosomes at a frequency of 0.0000096, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000637516 SCV000758978 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-21 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 232 of the BRCA2 protein (p.Tyr232His). The tyrosine residue is weakly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is present in population databases (rs398122572, ExAC 0.002%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 91465). 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 histidine 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.
Michigan Medical Genetics Laboratories,University of Michigan RCV000076982 SCV000267739 uncertain significance Breast-ovarian cancer, familial 2 2016-04-21 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000076982 SCV000108779 uncertain significance Breast-ovarian cancer, familial 2 2006-01-06 no assertion criteria provided clinical testing

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