ClinVar Miner

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

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Total submissions: 11
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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 likely pathogenic Hereditary melanoma 2020-10-29 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 49 of the CDKN2A (p16INK4a) 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 observed in individuals affected with melanoma and/or pancreatic cancer (PMID: 7987387, 16896043, 21462282, 26681309, Invitae). It has also been observed to segregate with disease, with enrichment of pancreatic cancer among individuals and families with this variant (Invitae). Greater than 95% of these individuals self report Hispanic ancestry (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 are conflicting or provide insufficient evidence to determine the effect of this variant on CDKN2A (p16INK4a) protein function (PMID: 7566978, 7647780, 8573142, 10719365, 10389768, 21462282). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000115331 SCV000212740 likely pathogenic Hereditary cancer-predisposing syndrome 2020-06-25 criteria provided, single submitter clinical testing The p.I49T variant (also known as c.146T>C), located in coding exon 1 of the CDKN2A gene, results from a T to C substitution at nucleotide position 146. The isoleucine at codon 49 is replaced by threonine, an amino acid with similar properties. This variant has been reported in patients with no family history of melanoma but who had a single primary melanoma or multiple primary melanomas (Berwick M et al. Eur. J. Cancer Prev. 2004 Feb;13:65-70; Begg CB et al. J. Natl. Cancer Inst. 2005 Oct;97:1507-15). It has also been reported in multiple familial melanoma cases, however, in one case, it did not completely segregate with disease (Hussussian CJ et al. Nat. Genet. 1994 Sep;8:15-21​; Puig S et al. Genet. Med. 2016 Jul;18:727-36). Multiple functional studies have demonstrated that this variant diminishes the binding activity of p16 to CDK4 and CDK6 and displays reduced ability to effect Rb dephosphorylation, however the degree of effect is shown to be more intermediate than other known pathogenic variants (Ranade K et al. Nat. Genet. 1995 May;10:114-6; Reymond A et al. Oncogene. 1995 Sep;11:1173-8; Yang R et al. Biochem. Biophys. Res. Commun. 1996 Jan;218:254-9; Walker GJ et al. Int. J. Cancer. 1999 Jul;82:305-12). In addition, this variant was ineffective at inhibiting cellular growth in a melanoma cell line and it demonstrated an abnormal pattern of cellular localization (Walker GJ et al. Int. J. Cancer. 1999 Jul;82:305-12). Internal structural analysis predicts that this amino acid position is involved in CDK4 binding and while other pathogenic missense mutations are also found at this location, the substitution of threonine at this position induces a milder perturbation on the structure than those variants (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic with moderate risk.
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
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000761151 SCV000891067 uncertain significance Osteoblastic osteosarcoma 2017-04-03 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115331 SCV000910705 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-11 criteria provided, single submitter clinical testing This variant replaces isoleucine with threonine at codon 49 of the CDKN2A (p16INK4A) protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported the variant protein to be partially to fully functional in CDK4/6 binding in yeast and mammalian assays (PMID: 7566978, 7647780, 8573142, 10389768, 10719365, 21462282), but the variant protein is non-functional in cell cycle or growth arrest assays (PMID: 10389768, 21462282). This variant has been reported in multiple individuals and families affected with melanoma (PMID: 7987387, 11687599, 15075790, 16234564, 16896043, 17218939, 18335566, 21085193, 21462282, 26681309). This variant has also been identified in 158/280824 chromosomes (157/35432 Latino chromosomes, 0.44%) by the Genome Aggregation Database (gnomAD). Although this variant has been observed in multiple individuals affected with melanoma, it occurs at a high allele frequency in the general population (0.44% in the Latino population). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212398 SCV001134100 uncertain significance not provided 2020-08-09 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001001912 SCV001339145 uncertain significance not specified 2021-05-03 criteria provided, single submitter clinical testing Variant summary: CDKN2A c.146T>C (p.Ile49Thr) results in a non-conservative amino acid change located in the Ankyrin repeat-containing domain (IPR020683) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00063 in 249454 control chromosomes. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDKN2A causing Cutaneous Malignant Melanoma phenotype (0.0003), suggesting that the variant may be benign. c.146T>C has been reported in the literature in individuals affected with Melanoma (e.g. Hussussian_1994, Begg_2005, Capanu_2008, Miller_2011, Puig_2016). Analysis of a multi-generation family did not show complete co-segregation of this variant and the disease (Hussussian_1994). In addition, this variant was also found in patients with HBOC, CRC, LS (e.g. Yurgelun_2015, Ricker_2017, Slavin_2018, Oliver_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (TP53 c.818G>A, p.Arg273His), providing supporting evidence for a benign role. Multiple experimental studies showed that this variant results in: decreased inhibition of cyclinD1/CDK4 and cyclin D1/CDK6 activity (Ranade_1995), decreased binding activity to CDK4 (Yang_1996), no effect on binding to the kinases but substantially diminished ability to inhibit cell growth and mis-localization (Walker_1999), loss of function in a cell cycle arrest assay (Miller_2011). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS n=7, likely pathogenic n=3). Based on the conflicting evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics RCV001292944 SCV001481651 likely pathogenic Melanoma and neural system tumor syndrome 2020-01-07 criteria provided, single submitter clinical testing This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in multiple patients with melanoma [PMID: 7987387, 17218939, 26681309, 28830827] Functional assays also showed impaired protein function caused by this variant [PMID: 7647780, 10389768, 21462282]

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