ClinVar Miner

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

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
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
Counsyl RCV000412396 SCV000488873 uncertain significance Melanoma-pancreatic cancer syndrome 2016-07-12 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000212398 SCV000805818 uncertain significance not provided 2017-10-12 criteria provided, single submitter clinical testing
Color RCV000115331 SCV000910705 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-03 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212398 SCV001134100 uncertain significance not provided 2018-10-23 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001001912 SCV001159666 uncertain significance not specified 2018-12-19 criteria provided, single submitter clinical testing The CDKN2A c.146T>C; p.Ile49Thr variant (rs199907548) is reported in the literature in individuals affected with melanoma or breast cancer (Hussussian 1994, Kurian 2014, Orlow 2007, Puig 2016, Taylor 2017). However, in one family this variant did not segregate with disease (Hussussian 1994), while melanoma was not reported in nine first-degree relatives of another carrier (Orlow 2007). This variant is found in the Latino population with an overall allele frequency of 0.44% (157/35432 alleles) in the Genome Aggregation Database. The isoleucine at codon 49 is moderately conserved, computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious, and another variant at this codon (p.Ile49Ser) has been reported in melanoma patients and is considered pathogenic (Orlow 2007, Taylor 2017). Functional analyses indicate that the p.Ile49Thr variant fails to arrest growth of melanoma or osteosarcoma cells like wildtype protein (Miller 2011, Walker 1999), and it exhibits roughly half of wildtype activity in an in vitro assay for inhibition of cyclin D1-CDK signaling (Ranade 1995). However, due to conflicting information, the clinical significance of the p.Ile49Thr variant is uncertain at this time. References: Hussussian CJ et al. Germline p16 mutations in familial melanoma. Nat Genet. 1994 Sep;8(1):15-21. Kurian AW et al. Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol. 2014 Jul 1;32(19):2001-9. Miller PJ et al. Classifying variants of CDKN2A using computational and laboratory studies. Hum Mutat. 2011 Aug;32(8):900-11. Orlow I et al. CDKN2A germline mutations in individuals with cutaneous malignant melanoma. J Invest Dermatol. 2007 May;127(5):1234-43. Puig S et al. Characterization of individuals at high risk of developing melanoma in Latin America: bases for genetic counseling in melanoma. Genet Med. 2016 Jul;18(7):727-36. Ranade K et al. Mutations associated with familial melanoma impair p16INK4 function. Nat Genet. 1995 May;10(1):114-6. Taylor NJ et al. Germline Variation at CDKN2A and Associations with Nevus Phenotypes among Members of Melanoma Families. J Invest Dermatol. 2017 Dec;137(12):2606-2612. Walker GJ et al. Functional reassessment of P16 variants using a transfection-based assay. Int J Cancer. 1999 Jul 19;82(2):305-12.
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000761151 SCV000891067 uncertain significance Osteoblastic Osteosarcoma 2017-04-03 no assertion criteria provided clinical testing

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