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

gnomAD frequency: 0.00002  dbSNP: rs587778187

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000122944	SCV000166202	uncertain significance	Familial melanoma	2025-02-02	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	likely benign	Hereditary cancer-predisposing syndrome	2024-02-29	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
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