ClinVar Miner

Submissions for variant NM_000075.4(CDK4):c.70C>T (p.Arg24Cys) (rs11547328)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000168188 SCV000218852 pathogenic Hereditary melanoma 2019-01-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 24 of the CDK4 protein (p.Arg24Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This sequence change has been reported in the literature and is not currently found in any individuals from population databases (rs11547328, no frequency). This sequence change has been reported to segregate with melanoma in several families (PMID: 8528263, 23384855). Experimental studies have shown that this missense change abolishes interaction of CDK4 with p16(INK4a) in vitro, causing the CDK4 protein to be less susceptible to inhibition by p16(INK4a) (PMID: 7652577). Experiments in mouse models showed that the Arg24Cys sequence change leads to increased CDK4 kinase activity in fibroblasts, and enables the cells to escape from replicative senescence. In agreement with the in vitro data, homozygous CDK4(R24C/R24C) mice developed tumors of various etiology (pancreas, pituitary, brain, mammary tissue, and skin) within 8 to 10 months of their life span (PMID: 11756559). For these reasons, this sequence change has been classified as Pathogenic.
Counsyl RCV000018436 SCV000488638 pathogenic Cutaneous malignant melanoma 3 2016-05-26 criteria provided, single submitter clinical testing
GeneDx RCV000484583 SCV000568686 pathogenic not provided 2016-04-26 criteria provided, single submitter clinical testing This pathogenic variant is denoted CDK4 c.70C>T at the cDNA level, p.Arg24Cys (R24C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant has been reported to segregate with melanoma in several melanoma families (Zuo 1996, Puntervoll 2013). Functional studies have shown that this variant disrupts binding with CDKN2A, resulting in resistance to CDKN2A inhibition and increased CDK4 kinase activity (Wolfel 1995, Rane 2002). CDK4 Arg24Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CDK4 Arg24Cys occurs at a position that is conserved across species and is located in the protein kinase domain (UniProt). In silico analyses are inconsistent regarding the effect this pathogenic variant may have on protein structure and function. Based on currently available evidence, we consider this variant to be pathogenic.
Color Health, Inc RCV000584153 SCV000689576 pathogenic Hereditary cancer-predisposing syndrome 2020-04-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000168188 SCV000695325 pathogenic Hereditary melanoma 2017-08-15 criteria provided, single submitter clinical testing Variant summary: The CDK4 c.70C>T (p.Arg24Cys) variant involves the alteration of a conserved nucleotide and is located in protein kinase domain of the protein (InterPro). 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/121378 control chromosomes from ExAC at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic CDK4 variant (0.00002). This variant has been reported in six unrelated cutaneous malignant melanoma families including evidence of cosegregation with disease (Zuo_1996, Ghiorzo_2012, Puntervoll_2013). In vivo mice-model study shows the recapitulation of melanoma phenotype (Rane_2002). The codon p.Arg24 is a mutational hot-spot in which another mutation p.Arg24His is known to be pathogenic. Multiple clinical diagnostic laboratories in ClinVar have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
OMIM RCV000018436 SCV000038718 risk factor Cutaneous malignant melanoma 3 1996-01-01 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438126 SCV000505860 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420489 SCV000505861 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426326 SCV000505862 likely pathogenic Multiple myeloma 2016-05-31 no assertion criteria provided literature only

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