ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.6601A>G (p.Thr2201Ala) (rs745945481)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165324 SCV000216047 uncertain significance Hereditary cancer-predisposing syndrome 2016-02-19 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);Insufficient or conflicting evidence;In silico models in agreement (benign)
Invitae RCV000205816 SCV000260494 likely benign Neurofibromatosis, type 1 2020-01-04 criteria provided, single submitter clinical testing
GeneDx RCV000681126 SCV000808584 uncertain significance not provided 2018-02-26 criteria provided, single submitter clinical testing This variant is denoted NF1 c.6601A>G at the cDNA level, p.Thr2201Ala (T2201A) at the protein level, and results in the change of a Threonine to an Alanine (ACG>GCG). Using alternate nomenclature, this variant has been reported as NF1 c.6664A>G (T222A). 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 prostate and lung cancer (Hovelson 2015). NF1 Thr2201Ala was observed at an allele frequency of 0.006% (17/277,112) 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 NF1 Thr2201Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001002410 SCV001160341 uncertain significance not specified 2019-02-16 criteria provided, single submitter clinical testing The NF1 c.6664A>G; p.Thr2222Ala variant (rs745945481), to our knowledge, is not described in the medical literature as a germline variant but is reported as a variant of uncertain significance by multiple laboratories in ClinVar (Variation ID: 185829). It is observed in the general population at a low overall frequency of 0.0057% (16/282734 alleles) in the Genome Aggregation Database. The threonine at codon 2222 is moderately conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is tolerated. However, due to the lack of clinical and functional data regarding this variant, its clinical significance cannot be determined with certainty.

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