ClinVar Miner

Submissions for variant NM_000075.4(CDK4):c.122A>G (p.Asn41Ser) (rs144890720)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122940 SCV000166198 uncertain significance Hereditary melanoma 2020-10-29 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 41 of the CDK4 protein (p.Asn41Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs144890720, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with melanoma, breast cancer, colorectal cancer, and suspected Lynch syndrome (PMID: 9311594, 25186627, 25980754, 28135145). ClinVar contains an entry for this variant (Variation ID: 135822). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
GeneDx RCV000589966 SCV000292532 uncertain significance not provided 2021-08-16 criteria provided, single submitter clinical testing Observed in individuals with a personal or family history of melanoma, breast and other cancers, or suspected Lynch syndrome (Guldberg 1997, Tung 2015, Yurgelun 2015, Pritchard 2018); Published functional studies are inconclusive: Does not disrupt CDK4 binding to CDKN2C or affect interaction with p16, cyclin D2, SEI-1 RM 29 or other CDK4 partner proteins; however, it may negatively impact binding with I-kappaB-alpha, an inhibitor of nuclear factor-kappaB (Li 2003, Li 2005, Zhong 2009, Rolland 2014); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32980694, 19139070, 24162924, 29641532, 25186627, 11828258, 29124743, 28575754, 26252490, 25416956, 19888216, 16201750, 25980754, 12731669, 12358822, 14621993, 9311594, 28135145)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235428 SCV000601002 uncertain significance not specified 2017-02-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV000572763 SCV000669084 likely benign Hereditary cancer-predisposing syndrome 2018-08-08 criteria provided, single submitter clinical testing In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s);Other data supporting benign classification
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589966 SCV000695313 likely benign not provided 2017-05-22 criteria provided, single submitter clinical testing Variant summary: The CDK4 c.122A>G (p.Asn41Ser) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant . This variant was found in 20/121396 control chromosomes at a frequency of 0.0001648, which is approximately 8 times the estimated maximal expected allele frequency of a pathogenic CDK4 variant (0.00002), suggesting this variant is likely a benign polymorphism. The variant has been reported in patients with Lynch syndrome and sporadic metastatic malignant melanomas in the literature, without strong evidence for causality. Analysis of a tumor derived cell line demonstrated equal expression of the mutant and wild-type CDK4 alleles, together with lack of functional p16 (Guldber_1997). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as likely benign until additional evidence becomes available.
Counsyl RCV000662895 SCV000785815 uncertain significance Cutaneous malignant melanoma 3 2017-12-11 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589966 SCV000888049 likely benign not provided 2020-05-13 criteria provided, single submitter clinical testing
Mendelics RCV000662895 SCV001138764 benign Cutaneous malignant melanoma 3 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000662895 SCV001266730 benign Cutaneous malignant melanoma 3 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

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