Submissions for variant NM_000075.4(CDK4):c.834T>C (p.Phe278=)

gnomAD frequency: 0.00013  dbSNP: rs115576923

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079786	SCV000260163	likely benign	Familial melanoma	2024-12-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000759742	SCV000528715	likely benign	not provided	2019-02-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000575437	SCV000669090	likely benign	Hereditary cancer-predisposing syndrome	2015-02-13	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759742	SCV000889272	benign	not provided	2022-09-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000424489	SCV000919119	likely benign	not specified	2017-12-11	criteria provided, single submitter	clinical testing	Variant summary: The CDK4 c.834T>C (p.Phe278Phe) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE site of SC35 and SRp40. However, these predictions have yet to be confirmed by functional studies. This variant was found in 13/277162 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.000458 (11/24022). This frequency is about 20 times the estimated maximal expected allele frequency of a pathogenic CDK4 variant (0.00002), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely benign.
Myriad Genetics, Inc.	RCV004786543	SCV005403349	benign	Melanoma, cutaneous malignant, susceptibility to, 3	2024-09-27	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
True Health Diagnostics	RCV000575437	SCV000787992	likely benign	Hereditary cancer-predisposing syndrome	2017-10-26	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003967549	SCV004783112	likely benign	CDK4-related disorder	2019-09-05	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).