12-57751563-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000075.4(CDK4):c.155G>A(p.Ser52Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000458 in 1,614,100 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S52R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

CDK4
NM_000075.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 5.76

Publications

4 publications found

Variant links:

COSMIC-nc: COSV106084389

Genes affected

CDK4 (HGNC:1773): (cyclin dependent kinase 4) The protein encoded by this gene is a member of the Ser/Thr protein kinase family. This protein is highly similar to the gene products of S. cerevisiae cdc28 and S. pombe cdc2. It is a catalytic subunit of the protein kinase complex that is important for cell cycle G1 phase progression. The activity of this kinase is restricted to the G1-S phase, which is controlled by the regulatory subunits D-type cyclins and CDK inhibitor p16(INK4a). This kinase was shown to be responsible for the phosphorylation of retinoblastoma gene product (Rb). Mutations in this gene as well as in its related proteins including D-type cyclins, p16(INK4a) and Rb were all found to be associated with tumorigenesis of a variety of cancers. Multiple polyadenylation sites of this gene have been reported. [provided by RefSeq, Jul 2008]

CDK4 Gene-Disease associations (from GenCC):

melanoma, cutaneous malignant, susceptibility to, 3
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
malignant pancreatic neoplasm
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

CDK4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 73 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK4	NM_000075.4 link	c.155G>A	p.Ser52Asn	missense_variant	Exon 2 of 8	ENST00000257904.11	NP_000066.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK4	ENST00000257904.11 link	c.155G>A	p.Ser52Asn	missense_variant	Exon 2 of 8	1	NM_000075.4	ENSP00000257904.5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251460

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000499

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.0000426

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000629

AC:

AN:

1112010

Other (OTH)

AF:

0.0000497

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000453

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Mar 03, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CDK4 c.155G>A (p.Ser52Asn) results in a 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 1.6e-05 in 251460 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.155G>A has been reported in the literature in one family affected with Melanoma (Holland_1999), however all affected members of the family also had a second (possibly) pathogenic variant (CDKN2A c.146T>G, p.Ile49Ser), which could explain the phenotype. In addition, co-occurrences with other pathogenic variants have been reported (CHEK2 c.1100delC, p.Thr367MetfsX15; in an internal LCA sample), providing supporting evidence for a benign role. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated using yeast two-hybrid assays that the variant doesn't significantly affect protein interactions (Zhong_2009, Lambert_2013, Rolland_2014). Four ClinVar submitters have assessed the variant since 2014: all submitters classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

Jul 18, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CDK4-related disorder

Uncertain:1

Mar 07, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CDK4 c.155G>A variant is predicted to result in the amino acid substitution p.Ser52Asn. This variant was found in two out of four patients from a family with melanoma; three out of four patients also carried a variant in the CDKN2A gene (Figure 2, Holland et al. 1999. PubMed ID: 10398427). The c.155G>A variant in CDK4 was also detected in one patient undergoing Lynch syndrome testing (Yurgelun et al. 2015. PubMed ID: 25980754) and in one child with B-ALL (Zhang et al. 2015. PubMed ID: 26580448). In vitro functional characterization showed that this variant does not perturb CDK4 binding to CDKN2C (Rolland et al. 2014. PubMed ID: 25416956). This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-58145346-C-T) and is interpreted as a variant of uncertain significance in Clinvar (https://www.ncbi.nlm.nih.gov/clinvar/variation/439046/?new_evidence=true). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

not provided

Uncertain:1

Feb 19, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in a hereditary melanoma family, who also harbored a CDKN2A variant (Ile49Ser), found to segregate with cancer, as well as in individuals with ovarian cancer or suspected of having Lynch syndrome (PMID: 10398427, 25980754, 34326862); Functional studies demonstrate that this variant does not significantly affect binding with CDKN2C or other protein interactions (PMID: 24162924, 25416956); In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25416956, 24162924, 19888216, 11828258, 22932448, 25980754, 10398427, 35113472, 34326862, 26580448)

Hereditary cancer-predisposing syndrome

Uncertain:1

Apr 25, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.S52N variant (also known as c.155G>A), located in coding exon 1 of the CDK4 gene, results from a G to A substitution at nucleotide position 155. The serine at codon 52 is replaced by asparagine, an amino acid with highly similar properties. This variant has been reported in two out of four individuals from a family with hereditary melanoma, however this family is also noted to carry a CDKN2A alteration (Ile49Ser), which was detected in three of the four individuals (Holland EA et al. Genes Chromosomes Cancer. 1999 Aug;25:339-48). This variant was also detected in 1/131 nodular melanoma patients and in 0/194 non-melanoma control patients (Stark MS et al. Br J Dermatol, 2024 Jan;190:199-206). Although this amino acid position lies near the cyclin binding site, it is not predicted to make direct contact with D type cyclins in the crystal structure, and although some models show that this alteration may perturb binding to CDKN2C, functional studies showed that this alteration behaved like wildtype with respect to CDKN2C, CDKN1B, CDC37 and HSP90 binding (Rolland T et al. Cell. 2014 Nov;159:1212-1226; Zhong Q et al. Mol. Syst. Biol. 2009 Nov;5:321; Lambert JP et al. Nat. Methods. 2013 Dec;10:1239-45). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

Familial melanoma

Uncertain:1

Dec 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 52 of the CDK4 protein (p.Ser52Asn). This variant is present in population databases (rs760719270, gnomAD 0.004%). This missense change has been observed in individual(s) with head and neck carcinoma, melanoma, and/or ovarian cancer (PMID: 10398427, 22932448, 25980754, 34326862). ClinVar contains an entry for this variant (Variation ID: 439046). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change does not substantially affect CDK4 function (PMID: 24162924, 25416956). 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.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

T;T;.;T;.

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

D;D;D;D;D

M_CAP

Uncertain

0.092

MetaRNN

Uncertain

0.47

T;T;T;T;T

MetaSVM

Benign

-0.36

MutationAssessor

Benign

0.0

.;L;.;.;.

PhyloP100

5.8

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.6

N;N;N;N;N

REVEL

Uncertain

0.37

Sift

Benign

0.096

T;D;T;T;T

Sift4G

Uncertain

0.0070

D;T;T;.;.

Vest4

0.85

ClinPred

0.82

GERP RS

4.3

PromoterAI

0.022

Neutral

(source)

Varity_R

0.79

gMVP

0.73

Mutation Taster

=20/80

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over