Submissions for variant NM_000075.4(CDK4):c.779T>A (p.Val260Glu)

gnomAD frequency: 0.00013  dbSNP: rs200215596

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656827	SCV000210931	uncertain significance	not provided	2023-08-30	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis supports a deleterious effect on splicing; Observed in individuals with breast cancer, thyroid cancer, or history concerning for Lynch Syndrome (Yurgelun et al., 2015; Bhai et al., 2021); This variant is associated with the following publications: (PMID: 23718828, 26252490, 25980754, 34326862)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000458248	SCV000547947	uncertain significance	Familial melanoma	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 260 of the CDK4 protein (p.Val260Glu). This variant is present in population databases (rs200215596, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 25980754, 34326862). ClinVar contains an entry for this variant (Variation ID: 182405). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CDK4 protein function with a negative predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160399	SCV000601013	uncertain significance	not specified	2017-05-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000565351	SCV000669091	likely benign	Hereditary cancer-predisposing syndrome	2019-05-06	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.
PreventionGenetics, part of Exact Sciences	RCV000656827	SCV000805812	uncertain significance	not provided	2018-01-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765100	SCV000896319	uncertain significance	Melanoma, cutaneous malignant, susceptibility to, 3	2018-10-31	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000458248	SCV002032316	uncertain significance	Familial melanoma	2021-11-11	criteria provided, single submitter	clinical testing	The CDK4 c c.779T>A (p.Val260Glu) missense change has a maximum subpopulation frequency of 0.012% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/12-58143005-A-T?dataset=gnomad_r2_1). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional studies. This variant has been reported in individuals with breast cancer (PMID: 25186627) and Lynch syndrome (PMID: 25980754). To our knowledge, this variant has not been reported in individuals with familial melanoma. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000765100	SCV004171442	uncertain significance	Melanoma, cutaneous malignant, susceptibility to, 3	2023-09-08	criteria provided, single submitter	clinical testing	The CDK4 c.779T>A (p.Val260Glu) missense change has a maximum subpopulation frequency of 0.012% 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 breast cancer (PMID: 25186627) and Lynch syndrome (PMID: 25980754). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000160399	SCV005202325	likely benign	not specified	2024-07-29	criteria provided, single submitter	clinical testing	Variant summary: CDK4 c.779T>A (p.Val260Glu) 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 0.00013 in 1613828 control chromosomes, predominantly at a frequency of 0.00017 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote (gnomAD v4.1.0). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 8.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDK4 causing Cutaneous Malignant Melanoma phenotype (2e-05). c.779T>A has been reported in the literature in individuals undergoing hereditary cancer testing, individuals with breast cancer or head and neck squamous cell carcinoma (examples: Tung_Cancer_2015, Bhai_FG_2021, Lechner_GM_2013) without strong evidence for or against pathogenicity. These report(s) 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: 25186627, 34326862, 23718828). ClinVar contains an entry for this variant (Variation ID: 182405). Based on the evidence outlined above, the variant was classified as likely benign.