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NM_000075.4(CDK4):c.122A>G (p.Asn41Ser)

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Interpretation:
Conflicting interpretations of pathogenicity​

Benign(2);Likely benign(3);Uncertain significance(5)

Review status:
criteria provided, conflicting interpretations
Submissions:
10 (Most recent: Nov 4, 2021)
Last evaluated:
Nov 3, 2021
Accession:
VCV000135822.12
Variation ID:
135822
Description:
single nucleotide variant
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NM_000075.4(CDK4):c.122A>G (p.Asn41Ser)

Allele ID
139534
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
12q14.1
Genomic location
12: 57751596 (GRCh38) GRCh38 UCSC
12: 58145379 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
P11802:p.Asn41Ser
NC_000012.11:g.58145379T>C
NC_000012.12:g.57751596T>C
... more HGVS
Protein change
N41S
Other names
-
Canonical SPDI
NC_000012.12:57751595:T:C
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
Exome Aggregation Consortium (ExAC) 0.00016
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00038
The Genome Aggregation Database (gnomAD), exomes 0.00011
The Genome Aggregation Database (gnomAD) 0.00013
The Genome Aggregation Database (gnomAD) 0.00016
Trans-Omics for Precision Medicine (TOPMed) 0.00020
Links
ClinGen: CA332390
UniProtKB: P11802#VAR_021152
dbSNP: rs144890720
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Uncertain significance 1 criteria provided, single submitter Oct 29, 2020 RCV000122940.9
Uncertain significance 1 criteria provided, single submitter Feb 18, 2017 RCV000235428.4
Likely benign 1 criteria provided, single submitter Aug 8, 2018 RCV000572763.1
Conflicting interpretations of pathogenicity 3 criteria provided, conflicting interpretations Aug 16, 2021 RCV000589966.4
Conflicting interpretations of pathogenicity 4 criteria provided, conflicting interpretations Nov 3, 2021 RCV000662895.4
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
CDK4 No evidence available No evidence available GRCh38
GRCh37
344 568

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Uncertain significance
(Oct 29, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary melanoma
Allele origin: germline
Invitae
Accession: SCV000166198.9
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (6)
Comment:
This sequence change replaces asparagine with serine at codon 41 of the CDK4 protein (p.Asn41Ser). The asparagine residue is moderately conserved and there is a … (more)
Uncertain significance
(Aug 16, 2021)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000292532.11
Submitted: (Sep 29, 2021)
Evidence details
Comment:
Observed in individuals with a personal or family history of melanoma, breast and other cancers, or suspected Lynch syndrome (Guldberg 1997, Tung 2015, Yurgelun 2015, … (more)
Uncertain significance
(Feb 18, 2017)
criteria provided, single submitter
Method: clinical testing
not specified
Allele origin: germline
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601002.1
Submitted: (Aug 01, 2017)
Evidence details
Publications
PubMed (4)
Likely benign
(May 22, 2017)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695313.1
Submitted: (Jan 25, 2018)
Evidence details
Publications
PubMed (3)
Comment:
Variant summary: The CDK4 c.122A>G (p.Asn41Ser) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant … (more)
Uncertain significance
(Dec 11, 2017)
criteria provided, single submitter
Method: clinical testing
Cutaneous malignant melanoma 3
Allele origin: unknown
Counsyl
Accession: SCV000785815.2
Submitted: (Jun 20, 2018)
Evidence details
Publications
PubMed (6)
Benign
(May 28, 2019)
criteria provided, single submitter
Method: clinical testing
Cutaneous malignant melanoma 3
Allele origin: unknown
Mendelics
Accession: SCV001138764.1
Submitted: (Oct 22, 2019)
Evidence details
Benign
(Apr 28, 2017)
criteria provided, single submitter
Method: clinical testing
Cutaneous malignant melanoma 3
Allele origin: germline
Illumina Clinical Services Laboratory,Illumina
Accession: SCV001266730.1
Submitted: (Feb 20, 2020)
Evidence details
Publications
PubMed (3)
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
Likely benign
(Aug 08, 2018)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Ambry Genetics
Accession: SCV000669084.3
Submitted: (Nov 30, 2020)
Evidence details
Publications
PubMed (6)
Comment:
In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s);Other data supporting benign classification
Likely benign
(May 13, 2020)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: unknown
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000888049.2
Submitted: (Dec 31, 2020)
Evidence details
Publications
PubMed (7)
Uncertain significance
(Nov 03, 2021)
criteria provided, single submitter
Method: clinical testing
Cutaneous malignant melanoma 3
Allele origin: germline
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002010278.1
Submitted: (Nov 04, 2021)
Evidence details

Functional evidence

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There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Citations for this variant

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Title Author Journal Year Link
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Nykamp K Genetics in medicine : official journal of the American College of Medical Genetics 2017 PMID: 28492532
Pathogenic variant burden in the ExAC database: an empirical approach to evaluating population data for clinical variant interpretation. Kobayashi Y Genome medicine 2017 PMID: 28166811
Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. Yurgelun MB Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2017 PMID: 28135145
Analysing the Effect of Mutation on Protein Function and Discovering Potential Inhibitors of CDK4: Molecular Modelling and Dynamics Studies. N N PloS one 2015 PMID: 26252490
Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. Yurgelun MB Gastroenterology 2015 PMID: 25980754
Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Tung N Cancer 2015 PMID: 25186627
Mapping differential interactomes by affinity purification coupled with data-independent mass spectrometry acquisition. Lambert JP Nature methods 2013 PMID: 24162924
Edgetic perturbation models of human inherited disorders. Zhong Q Molecular systems biology 2009 PMID: 19888216
Genome-wide analysis to predict protein sequence variations that change phosphorylation sites or their corresponding kinases. Ryu GM Nucleic acids research 2009 PMID: 19139070
Dissection of CDK4-binding and transactivation activities of p34(SEI-1) and comparison between functions of p34(SEI-1) and p16(INK4A). Li J Biochemistry 2005 PMID: 16201750
An NF-kappaB-specific inhibitor, IkappaBalpha, binds to and inhibits cyclin-dependent kinase 4. Li J Biochemistry 2003 PMID: 14621993
Complete scanning of the CDK4 gene by denaturing gradient gel electrophoresis: a novel missense mutation but low overall frequency of mutations in sporadic metastatic malignant melanoma. Guldberg P International journal of cancer 1997 PMID: 9311594

Text-mined citations for rs144890720...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 27, 2021