ClinVar Miner

Submissions for variant NM_000075.4(CDK4):c.155G>A (p.Ser52Asn) (rs760719270)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000506470 SCV000601003 uncertain significance not specified 2017-07-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV000568365 SCV000669100 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-28 criteria provided, single submitter clinical testing The p.S52N variant (also known as c.155G>A), located in coding exon 1 of the CDK4 gene, results from a G to A substitution at nucleotide position 155. The serine at codon 52 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in two out of four individuals from a family with hereditary melanoma, however this family is also noted to carry a CDKN2A alteration (Ile49Ser), which was detected in three of the four individuals (Holland EA et al. Genes Chromosomes Cancer. 1999 Aug;25:339-48). Although this amino acid position lies near the cyclin binding site, it is not predicted to make direct contact with D type cyclins in the crystal structure, and although some models show that this alteration may perturb binding to CDKN2C, functional studies showed that this alteration behaved like wildtype with respect to CDKN2C, CDKN1B, CDC37 and HSP90 binding (Rolland T et al. Cell. 2014 Nov;159:1212-1226; Zhong Q et al. Mol. Syst. Biol. 2009 Nov;5:321; Lambert JP et al. Nat. Methods. 2013 Dec;10:1239-45). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001049238 SCV001213279 uncertain significance Hereditary melanoma 2020-10-24 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 52 of the CDK4 protein (p.Ser52Asn). The serine residue is moderately conserved and there is a small physicochemical difference between serine and asparagine. This variant is present in population databases (rs760719270, ExAC 0.006%). This variant has been observed in several individuals affected with melanoma and head and neck carcinoma (PMID: 10398427, 22932448), and in an individual undergoing testing for Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 439046). This variant has been reported not to substantially affect CDK4 protein function (PMID: 24162924, 25416956). 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.

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