ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.434T>C (p.Ile145Thr) (rs730881680)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160418 SCV000210951 uncertain significance not provided 2018-06-07 criteria provided, single submitter clinical testing This variant is denoted CDKN2A c.434T>C at the cDNA level, p.Ile145Thr (I145T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATA>ACA). This variant was identified in an individual undergoing multigene hereditary cancer panel testing due to a personal history of a Lynch syndrome-related cancer and/or polyps (Yurgelun 2015). CDKN2A Ile145Thr was not observed 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 CDKN2A Ile145Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000200632 SCV000254245 uncertain significance Hereditary melanoma 2020-10-30 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 145 of the CDKN2A (p16INK4a) protein (p.Ile145Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CDKN2A (p16INK4a)-related disease. ClinVar contains an entry for this variant (Variation ID: 182420). 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 and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional 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.
Color Health, Inc RCV000771213 SCV000903253 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-16 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with threonine at codon 145 of the CDKN2A (p16INK4A) protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Lynch syndrome–associated cancer and/or polyps (PMID: 25980754). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000771213 SCV001184060 likely benign Hereditary cancer-predisposing syndrome 2020-05-13 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification

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