ClinVar Miner

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

gnomAD frequency: 0.00002  dbSNP: rs587778187
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122944 SCV000166202 uncertain significance Familial melanoma 2024-01-16 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 221 of the CDK4 protein (p.Asp221Asn). This variant is present in population databases (rs587778187, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CDK4-related conditions. ClinVar contains an entry for this variant (Variation ID: 133876). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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 2023-06-01 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 alteration was detected in a cohort of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). 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 2022-03-16 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 24728327, 20668451)
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 2022-12-23 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 individuals with breast cancer and brain metastasis without evidence of causality (Guindalini_2022, Diossy_2018). 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 (n=5) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl RCV000662616 SCV000785278 uncertain significance Melanoma, cutaneous malignant, susceptibility to, 3 2017-06-27 criteria provided, single submitter clinical testing
Mendelics RCV000662616 SCV000838660 uncertain significance Melanoma, cutaneous malignant, susceptibility to, 3 2018-07-02 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000590321 SCV002821727 uncertain significance not provided 2022-12-01 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000662616 SCV004020061 uncertain significance Melanoma, cutaneous malignant, susceptibility to, 3 2023-03-07 criteria provided, single submitter clinical testing This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
ITMI RCV000120536 SCV000084689 not provided not specified 2013-09-19 no assertion provided reference population

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