Submissions for variant NM_000075.4(CDK4):c.625C>T (p.Arg209Cys)

gnomAD frequency: 0.00029  dbSNP: rs140644696

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001086259	SCV000166201	likely benign	Familial melanoma	2025-02-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130933	SCV000185845	likely benign	Hereditary cancer-predisposing syndrome	2018-06-15	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	RCV000586938	SCV000210930	uncertain significance	not provided	2024-12-30	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26252490, 26534844, 28060055, 25801821, 28380455, 26580448, 28726808, 25186627, 27640074, 30374176, 33281875, 34130653, 30426508)
Counsyl	RCV000409800	SCV000488928	uncertain significance	Melanoma, cutaneous malignant, susceptibility to, 3	2016-07-19	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586938	SCV000601007	likely benign	not provided	2023-05-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000235157	SCV000695320	likely benign	not specified	2023-06-05	criteria provided, single submitter	clinical testing	Variant summary: CDK4 c.625C>T (p.Arg209Cys) results in a non-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 0.00035 in 251492 control chromosomes, predominantly within Northwestern European (at a frequency of 0.0008) and Swedish European subpopulations (at a frequency of 0.0008) in the gnomAD database (v2.1). These observed subpopulation frequencies are approximately 40 fold higher than the estimated maximal expected allele frequency for a pathogenic variant in CDK4 causing Cutaneous Malignant Melanoma phenotype (i.e. 8e-04 vs. 2e-05), strongly suggesting that the variant is a benign polymorphism found primarily in European subpopulations. The variant, c.625C>T, has been reported in the literature in an individual affected with melanoma (e.g., Borroni 2017), and other individuals affected with pancreatic (e.g., Chaffee 2018) breast cancer (e.g., Li 2016, Tung 2015, Schubert_2019), and co-occurring breast and thyroid cancer (e.g., Bakos_2021), although with limited information (i.e. lack of co-occurrence and cosegregation data); moreover, four of these breast cancer cases were of western/northern European ancestry. These reports therefore 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. The following publications have been ascertained in the context of this evaluation (PMID: 28060055, 28726808, 26534844, 27640074, 26252490, 25186627, 26580448, 34130653, 30426508). Ten ClinVar submitters (evaluation after 2014) have cited the variant and classified it as VUS (n=6) and likely benign (n=4). At-least one additional submitter has re-classified this variant from a VUS to likely benign since its previous evaluation. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000409800	SCV000891027	uncertain significance	Melanoma, cutaneous malignant, susceptibility to, 3	2023-08-30	criteria provided, single submitter	clinical testing	The CDK4 c.625C>T (p.Arg209Cys) missense change has a maximum subpopulation frequency of 0.065% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with pancreatic cancer (PMID: 28726808) and breast cancer (PMID: 25186627, 26534844). To our knowledge, this variant has not been reported in individuals with familial melanoma. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000586938	SCV002010276	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130933	SCV002534257	likely benign	Hereditary cancer-predisposing syndrome	2021-02-17	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000235157	SCV002550003	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000409800	SCV004020048	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.
True Health Diagnostics	RCV000130933	SCV000787990	uncertain significance	Hereditary cancer-predisposing syndrome	2018-03-02	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000586938	SCV001798568	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000586938	SCV001971655	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004745204	SCV005352417	uncertain significance	CDK4-related disorder	2024-09-01	no assertion criteria provided	clinical testing	The CDK4 c.625C>T variant is predicted to result in the amino acid substitution p.Arg209Cys. This variant has been reported in individuals with breast and/or ovarian cancer (Supplementary Info 2, Cohort 1 VUS, Tung et al. 2015. PubMed ID: 25186627; Li et al. 2016. PubMed ID: 26534844), melanoma (Borroni et al. 2017. PubMed ID: 28060055), and pancreatic cancer (Supplemental Tale 2, Chaffee et al. 2018. PubMed ID: 28726808). This variant was also reported in an study of cutaneous malignant melanoma genes in individuals with Parkinson’s disease (Supplemental Table 6, Lubbe et al. 2016. PubMed ID: 27640074). However, this variant has also been reported in unaffected family members and/or control populations (Lubbe et al. 2016. PubMed ID: 27640074; Borroni et al. 2017. PubMed ID: 28060055). This variant is reported in 0.065% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/135825/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.