Submissions for variant NM_000075.4(CDK4):c.763C>T (p.Arg255Cys)

gnomAD frequency: 0.00002  dbSNP: rs587778188

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000120537	SCV000601012	uncertain significance	not specified	2016-08-31	criteria provided, single submitter	clinical testing
Invitae	RCV000536177	SCV000637384	likely benign	Familial melanoma	2024-01-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000573723	SCV000669127	likely benign	Hereditary cancer-predisposing syndrome	2023-03-02	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
GeneKor MSA	RCV000573723	SCV000821982	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000988867	SCV001138761	uncertain significance	Melanoma, cutaneous malignant, susceptibility to, 3	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000988867	SCV001272969	benign	Melanoma, cutaneous malignant, susceptibility to, 3	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120537	SCV002572398	likely benign	not specified	2022-08-29	criteria provided, single submitter	clinical testing	Variant summary: CDK4 c.763C>T (p.Arg255Cys) 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 damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.3e-05 in 281996 control chromosomes (gnomAD), predominantly at a frequency of 0.0007 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 35 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 East Asian origin. c.763C>T has been reported in the literature in individuals affected with Gastric Cancer (Choi_2021) and suspected hereditary cancer predisposition (Tsaousis_2019). 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 have assessed the variant since 2014: four classify the variant as uncertain significance, one as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as likely benign.
ITMI	RCV000120537	SCV000084690	not provided	not specified	2013-09-19	no assertion provided	reference population