Submissions for variant NM_000075.4(CDK4):c.684-4A>T

gnomAD frequency: 0.00016  dbSNP: rs370609910

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130918	SCV000185828	benign	Hereditary cancer-predisposing syndrome	2019-04-05	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081858	SCV000253071	likely benign	Familial melanoma	2025-01-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000379030	SCV000380488	benign	Melanoma, cutaneous malignant, susceptibility to, 3	2018-01-13	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.
GeneDx	RCV000587409	SCV000517464	likely benign	not provided	2020-03-27	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25980754)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587409	SCV000695323	benign	not provided	2016-10-21	criteria provided, single submitter	clinical testing	Variant summary: The CDK4 c.684-4A>T variant involves the alteration of a non-conserved intronic nucleotide with 5/5 splice prediction tools predict no significant impact on normal splicing and ESE finder predicting alterations to ESE binding, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 21/121132 (1/5767), predominantly in the European (Non-Finnish) cohort, 19/66612 (1/3506), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic CDK4 variant of 1/50000. Therefore, suggesting this is likely a benign polymorphism found primarily in population(s) of European (Non-Finnish) origin. The variant of interest has been reported in affected individuals via publications, however, cosegregation data was not provided. Clinical diagnostic laboratories have cited the variant with conflicting classifications "uncertain siginficance" or "likely benign," without any additional information to provide an independent evaluation. Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Benign.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002281958	SCV002570213	likely benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587409	SCV002774201	benign	not provided	2023-03-22	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000379030	SCV005405333	likely benign	Melanoma, cutaneous malignant, susceptibility to, 3	2024-09-26	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing.