Submissions for variant NM_000075.4(CDK4):c.776C>T (p.Ser259Leu)

gnomAD frequency: 0.00007  dbSNP: rs201617914

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000587659	SCV000149237	uncertain significance	not provided	2024-10-22	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with personal or family history of leukemia, ovarian, or other cancers (PMID: 26580448, 25318351, 30093976, 36243179); This variant is associated with the following publications: (PMID: 31766881, 24755471, 30093976, 26252490, 26580448, 25318351, 30851086, 36243179)
Ambry Genetics	RCV000115328	SCV000213859	likely benign	Hereditary cancer-predisposing syndrome	2019-04-16	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	RCV000195817	SCV000254234	likely benign	Familial melanoma	2024-01-31	criteria provided, single submitter	clinical testing
Counsyl	RCV000409921	SCV000489123	uncertain significance	Melanoma, cutaneous malignant, susceptibility to, 3	2016-08-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004525828	SCV000695329	likely benign	not specified	2024-03-05	criteria provided, single submitter	clinical testing	Variant summary: CDK4 c.776C>T (p.Ser259Leu) 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 benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 250518 control chromosomes, predominantly at a frequency of 0.00018 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDK4 causing Cutaneous Malignant Melanoma phenotype (2e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant was found in one patient who met the health insurance criteria for BRCA1/2 or Lynch syndrome gene testing, however specific clinical information and strong evidence for pathogenicity was not provided in this report (Yorczyk_2015). The variant was also reported in a pediatric cancer patient, again, lacking strong evidence for causality (Zhang_2015). In vitro/vivo studies assessing the impact the variant may have on the function of CDK4 were not published at the time of classification. The following publications have been ascertained in the context of this evaluation (PMID: 25318351, 26252490, 24755471, 26580448). ClinVar contains an entry for this variant (Variation ID: 127520). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics	RCV000409921	SCV000838658	benign	Melanoma, cutaneous malignant, susceptibility to, 3	2023-08-22	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000760999	SCV000890914	uncertain significance	Ewing sarcoma	2016-12-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587659	SCV001470483	likely benign	not provided	2019-12-24	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115328	SCV002534260	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-06	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000409921	SCV004020052	uncertain significance	Melanoma, cutaneous malignant, susceptibility to, 3	2023-03-07	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
PreventionGenetics, part of Exact Sciences	RCV004745186	SCV000805811	uncertain significance	CDK4-related disorder	2024-07-22	no assertion criteria provided	clinical testing	The CDK4 c.776C>T variant is predicted to result in the amino acid substitution p.Ser259Leu. This variant was reported as uncertain in a cohort of patients with hereditary predisposition to cancer (Yorczyk et al. 2014. PubMed ID: 25318351), in a patient with breast cancer (Xie et al. 2019. PubMed ID: 30851086), and in a patient with ovarian cancer (Chan et al. 2018. PubMed ID: 30093976). This variant was predicted to be neutral using computational methods to analyze the effects of nsSNPs on protein function (Nagasundaram et al. 2015. PubMed ID: 26252490). This variant is reported in 0.017% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127520/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.