ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.146T>C (p.Ile49Thr) (rs199907548)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115331 SCV000212740 likely pathogenic Hereditary cancer-predisposing syndrome 2017-12-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000761151 SCV000891067 uncertain significance Osteoblastic Osteosarcoma 2017-04-03 no assertion criteria provided clinical testing
Color RCV000115331 SCV000910705 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-03 criteria provided, single submitter clinical testing
Counsyl RCV000412396 SCV000488873 uncertain significance Melanoma-pancreatic cancer syndrome 2016-07-12 criteria provided, single submitter clinical testing
GeneDx RCV000212398 SCV000149240 uncertain significance not provided 2018-12-28 criteria provided, single submitter clinical testing This variant is denoted CDKN2A c.146T>C at the cDNA level, p.Ile49Thr (I49T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATC>ACC). This variant has been reported in individuals with sporadic and familial melanoma, but the variant did not completely segregate with disease in at least one family (Hussussian 1994, Berwick 2004, Orlow 2007, Puig 2016, Goldstein 2018). CDKN2A Ile49Thr has also been observed in individuals with breast cancer and in an individual with penile squamous cell carcinoma (Kurian 2014, McDaniel 2015, Tung 2015). Functional assays have demonstrated mixed results regarding this variant?s effect on binding to CDK4 and ability to inhibit cell growth (Ranade 1995, Reymond 1995, Walker 1999, Lal 2000, Miller 2011). CDKN2A Ile49Thr was observed with an allele frequency of 0.44% (152/34,412) in individuals of Latino ancestry in large population cohorts (Lek 2016). CDKN2A Ile49Thr is located in the ANK2 repeat domain (UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether CDKN2A Ile49Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000122945 SCV000166203 uncertain significance Hereditary cutaneous melanoma 2019-01-02 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 49 of the CDKN2A protein (p.Ile49Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs199907548, ExAC 0.5%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). However, all of these individuals are from the Latino sub-population of ExAC. This variant has been reported in individuals and families affected with melanoma (PMID: 7987387, 16896043, 21462282, 26681309). However, the information is insufficient at this time to determine if this variant segregates with melanoma in these families. It has also been observed in several individuals with a personal and/or family history of pancreatic cancer; greater than 95% of these individuals are self-reported as being Hispanic (Invitae). This variant is also known as c.140T>C (p.Ile41Thr) in the literature. ClinVar contains an entry for this variant (Variation ID: 127523). Experimental studies do not agree on the impact of this missense change on p16INK4a protein binding affinity with CDK4 and CDK6 (PMID: 7566978, 7647780, 8573142, 10719365, 10389768, 21462282). Some of these experimental studies report different degrees of reduced cell growth inhibition, even in the absence of reduced binding to CDK4 and CDK6 (PMID: 10389768, 21462282). The clinical significance of these data is uncertain at this time. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Although this variant is present in the ExAC database at a high frequency in the Latino population, there may be an association with this variant and pancreatic cancer in this population. However, without additional information, it has been classified as a Variant of Uncertain Significance.
PreventionGenetics RCV000212398 SCV000805818 uncertain significance not provided 2017-10-12 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.