ClinVar Miner

Submissions for variant NM_000075.4(CDK4):c.661G>A (p.Asp221Asn) (rs587778187)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122944 SCV000166202 uncertain significance Hereditary melanoma 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 221 of the CDK4 protein (p.Asp221Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs587778187, ExAC 0.006%). This variant has not been reported in the literature in individuals with CDK4-related disease. ClinVar contains an entry for this variant (Variation ID: 133876). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.
Ambry Genetics RCV000130883 SCV000185789 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-10 criteria provided, single submitter clinical testing The p.D221N variant (also known as c.661G>A), located in coding exon 5 of the CDK4 gene, results from a G to A substitution at nucleotide position 661. The aspartic acid at codon 221 is replaced by asparagine, an amino acid with highly similar properties. 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.
GeneDx RCV000590321 SCV000567218 uncertain significance not provided 2018-10-04 criteria provided, single submitter clinical testing This variant is denoted CDK4 c.661G>A at the cDNA level, p.Asp221Asn (D221N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAC>AAC). This variant was identified in 1/331 healthy European individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. CDK4 Asp221Asn was observed at an allele frequency of 0.011% (14/126,698) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the protein kinase domain (UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether CDK4 Asp221Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000120536 SCV000601010 likely benign not specified 2017-07-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000120536 SCV000695322 likely benign not specified 2020-07-02 criteria provided, single submitter clinical testing Variant summary: CDK4 c.661G>A (p.Asp221Asn) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251442 control chromosomes, predominantly at a frequency of 0.00011 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDK4 causing Cutaneous Malignant Melanoma phenotype (2e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.661G>A has been reported in the literature in one individual with primary breast cancer/brain metastasis pairs (Diossy_2018) and also reported as a somatic variant in one lung cancer sample (Kan_2010). These reports do not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (5x) and likely benign (1x). Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl RCV000662616 SCV000785278 uncertain significance Cutaneous malignant melanoma 3 2017-06-27 criteria provided, single submitter clinical testing
Mendelics RCV000662616 SCV000838660 uncertain significance Cutaneous malignant melanoma 3 2018-07-02 criteria provided, single submitter clinical testing
ITMI RCV000120536 SCV000084689 not provided not specified 2013-09-19 no assertion provided reference population

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