Submissions for variant NM_000075.4(CDK4):c.829A>G (p.Thr277Ala)

dbSNP: rs767343306

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000214741	SCV000273790	likely benign	Hereditary cancer-predisposing syndrome	2024-11-19	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000638985	SCV000760543	uncertain significance	Familial melanoma	2024-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 277 of the CDK4 protein (p.Thr277Ala). This variant is present in population databases (rs767343306, gnomAD 0.0009%). 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: 230297). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CDK4 protein function with a negative predictive value of 95%. 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.
GeneDx	RCV002305465	SCV002599488	uncertain significance	not provided	2022-05-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate disrupted p16 binding; however, the clone harboring this variant also harbored a second CDK4 variant making it difficult to determine the individual contribution of this variant (Mori 2003); This variant is associated with the following publications: (PMID: 12731669)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003444222	SCV004171420	uncertain significance	Melanoma, cutaneous malignant, susceptibility to, 3	2023-11-14	criteria provided, single submitter	clinical testing	The CDK4 c.829A>G (p.Thr277Ala) missense change has a maximum subpopulation frequency of 0.00088% 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. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002305465	SCV004221631	uncertain significance	not provided	2023-07-05	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported to disrupt binding to the CDK4 inhibitor p16INK4a (PMID: 12731669 (2002)), however additional studies are required to determine the global effect of this variant on CDK4 protein function. The frequency of this variant in the general population, 0.000024 (2/251444 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.