Submissions for variant NM_000075.4(CDK4):c.132_143del (p.Gly45_Gly48del)

dbSNP: rs749094206

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478208	SCV000566941	uncertain significance	not provided	2022-12-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 4 amino acids in a non-repeat region; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV000567506	SCV000669143	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-15	criteria provided, single submitter	clinical testing	The c.132_143del12 variant (also known as p.G45_G48del) is located in coding exon 1 of the CDK4 gene. This variant results from an in-frame AGGTGGAGGAGG deletion at nucleotide positions 132 to 143. This results in the in-frame deletion of four glycine residues at codons 45 to 48. The deleted amino acid positions are somewhat well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Mendelics	RCV000709233	SCV000838664	uncertain significance	Melanoma, cutaneous malignant, susceptibility to, 3	2018-07-02	criteria provided, single submitter	clinical testing
Invitae	RCV001220185	SCV001392161	uncertain significance	Familial melanoma	2023-12-12	criteria provided, single submitter	clinical testing	This variant, c.132_143del, results in the deletion of 4 amino acid(s) of the CDK4 protein (p.Gly45_Gly48del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs749094206, gnomAD 0.01%). 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: 419254). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509400	SCV002819328	uncertain significance	not specified	2022-12-08	criteria provided, single submitter	clinical testing	Variant summary: CDK4 c.132_143del12 (p.Gly45_Gly48del) results in an in-frame deletion that is predicted to remove four amino acids from the encoded protein. The variant allele was found at a frequency of 1.6e-05 in 251480 control chromosomes. To our knowledge, no occurrence of c.132_143del12 in individuals affected with Cutaneous Malignant Melanoma and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS.