Submissions for variant NM_000075.4(CDK4):c.777G>A (p.Ser259=)

gnomAD frequency: 0.00001  dbSNP: rs3211622

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000422425	SCV000512542	benign	not specified	2015-09-15	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000569838	SCV000669086	likely benign	Hereditary cancer-predisposing syndrome	2015-04-29	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589016	SCV000695330	likely benign	not provided	2016-04-11	criteria provided, single submitter	clinical testing	Variant summary: The variant of interest causes a synonymous change involving a non-conserved nucleotide with 4/5 in silico tools via Alamut predicting no significant effect on splicing, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 4/120492 (1/30120), which exceeds the predicted maximum expected allele frequency for a pathogenic CDK4 variant of 1/50000. However, these observations need to be cautiously considered due to the cohort including individuals that could harbor a CDK4-causing phenotype. In addition, the variant of interest, to our knowledge, has not been reported in affected individuals via publications and/or reputable databases/clinical laboratories. Therefore, taking all available lines of evidence into consideration the variant of interest is classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001443022	SCV001645982	likely benign	Familial melanoma	2025-01-23	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004791449	SCV005405072	benign	Melanoma, cutaneous malignant, susceptibility to, 3	2024-09-26	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.