ClinVar Genomic variation as it relates to human health
NM_000075.4(CDK4):c.122A>G (p.Asn41Ser)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(6); Benign(2); Likely benign(5)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000075.4(CDK4):c.122A>G (p.Asn41Ser)
Variation ID: 135822 Accession: VCV000135822.37
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q14.1 12: 57751596 (GRCh38) [ NCBI UCSC ] 12: 58145379 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 8, 2017 May 1, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000075.4:c.122A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000066.1:p.Asn41Ser missense NC_000012.12:g.57751596T>C NC_000012.11:g.58145379T>C NG_007484.2:g.5786A>G LRG_490:g.5786A>G LRG_490t1:c.122A>G P11802:p.Asn41Ser - Protein change
- N41S
- Other names
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- Canonical SPDI
- NC_000012.12:57751595:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00011
The Genome Aggregation Database (gnomAD) 0.00013
Exome Aggregation Consortium (ExAC) 0.00016
Trans-Omics for Precision Medicine (TOPMed) 0.00020
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00038
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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CDK4 | No evidence available | No evidence available |
GRCh38 GRCh37 |
550 | 1049 | |
LOC130008148 | - | - | - | GRCh38 | - | 104 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely benign (1) |
criteria provided, single submitter
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Jan 31, 2024 | RCV000122940.15 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Apr 10, 2023 | RCV000235428.14 | |
Likely benign (1) |
criteria provided, single submitter
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Aug 8, 2018 | RCV000572763.4 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Nov 19, 2023 | RCV000589966.16 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Nov 7, 2023 | RCV000662895.13 | |
Likely benign (1) |
criteria provided, single submitter
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Mar 18, 2023 | RCV003935172.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Dec 11, 2017)
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criteria provided, single submitter
Method: clinical testing
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Melanoma, cutaneous malignant, susceptibility to, 3
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000785815.2
First in ClinVar: Jul 15, 2018 Last updated: Jul 15, 2018 |
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Benign
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Melanoma, cutaneous malignant, susceptibility to, 3
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001138764.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Benign
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Melanoma, cutaneous malignant, susceptibility to, 3
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001266730.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
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)
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, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. (less)
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Uncertain significance
(Nov 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002067752.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Likely benign
(Apr 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695313.3
First in ClinVar: Mar 17, 2018 Last updated: Jun 03, 2023 |
Comment:
Variant summary: CDK4 c.122A>G (p.Asn41Ser) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four … (more)
Variant summary: CDK4 c.122A>G (p.Asn41Ser) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 251484 control chromosomes (gnomAD). The observed variant frequency is approximately 5-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 benign. c.122A>G has been reported in the literature in individuals affected with Cutaneous Malignant Melanoma, Lynch syndrome and breast cancer (e.g. Guldberg_1997, Tung_2015, Yurgelun_2015, Pritchard_2018). These reports do not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma. A co-occurrence with a pathogenic variant has been reported (SDHB c.268C>T, p.R90X; Beaubier_2019). Experimental evidence evaluating an impact on protein function demonstrated the variant does not affect interaction with p16, the RM29 mutant of SEI-1, cyclin D2 and other INK4 proteins but may contribute negatively to I-kappaB-alpha binding (Li_2003, Li_2005). Nine submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=4) or benign/likely benign (n=6). Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Uncertain significance
(Nov 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002010278.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
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Uncertain significance
(Mar 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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Melanoma, cutaneous malignant, susceptibility to, 3
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004020044.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
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.
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Uncertain significance
(Nov 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000292532.15
First in ClinVar: Jul 24, 2016 Last updated: Nov 25, 2023 |
Comment:
Observed in individuals with a personal or family history of melanoma, breast, or other cancers (PMID: 9311594, 25186627, 25980754, 29641532); Published functional studies are inconclusive: … (more)
Observed in individuals with a personal or family history of melanoma, breast, or other cancers (PMID: 9311594, 25186627, 25980754, 29641532); Published functional studies are inconclusive: does not disrupt CDK4 binding to CDKN2C or affect interaction with p16, cyclin D2, SEI-1 RM 29 or other CDK4 partner proteins; however, it may negatively impact binding with I-kappaB-alpha, an inhibitor of nuclear factor-kappaB (PMID: 14621993, 19888216, 25416956); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12358822, 28575754, 25186627, 29641532, 29124743, 11828258, 19888216, 28135145, 9311594, 14621993, 12731669, 25980754, 16201750, 25416956, 26252490, 19139070, 24162924, 32980694, 34426522, Tabar2022[article], 35113472, 31570899, 36243179) (less)
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Likely benign
(Dec 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000888049.4
First in ClinVar: Mar 13, 2019 Last updated: Jan 06, 2024 |
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Likely benign
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial melanoma
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000166198.12
First in ClinVar: Jun 16, 2014 Last updated: Feb 20, 2024 |
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Uncertain significance
(Nov 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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Melanoma, cutaneous malignant, susceptibility to, 3
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004564198.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The CDK4 c.122A>G; p.Asn41Ser variant (rs144890720) is reported in the literature in individuals affected with melanoma, colorectal and breast cancer but without clear disease association … (more)
The CDK4 c.122A>G; p.Asn41Ser variant (rs144890720) is reported in the literature in individuals affected with melanoma, colorectal and breast cancer but without clear disease association (Guldberg 1997, Pritchard 2018, Tung 2015, Yurgelun 2017). This variant has also been reported with a known pathogenic mutation in another gene (Beaubier 2019). This variant is also reported in ClinVar (Variation ID: 135822) and is found in the general population with an overall allele frequency of 0.01% (32/282802 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is neutral (REVEL: 0.113) and functional analyses of the variant protein show similar protein interactions compared to wild-type but suggest that the affinity between I-kappaB-alpha may be increased which negatively effects binding (Li 2003, Li 2005). While the functional analyses suggest a benign role, due to limited clinical information, the significance of this variant is uncertain at this time. References: Beaubier N et al. Integrated genomic profiling expands clinical options for patients with cancer. Nat Biotechnol. 2019 Nov;37(11):1351-1360. PMID: 31570899. Guldberg P et al. 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. Int J Cancer. 1997 Sep 4;72(5):780-3. PMID: 9311594. Li J et al. An NF-kappaB-specific inhibitor, IkappaBalpha, binds to and inhibits cyclin-dependent kinase 4. Biochemistry. 2003 Nov 25;42(46):13476-83. PMID: 14621993. Li J et al. Dissection of CDK4-binding and transactivation activities of p34(SEI-1) and comparison between functions of p34(SEI-1) and p16(INK4A). Biochemistry. 2005 Oct 11;44(40):13246-56. PMID: 16201750. Pritchard AL et al. Germline mutations in candidate predisposition genes in individuals with cutaneous melanoma and at least two independent additional primary cancers. PLoS One. 2018 Apr 11;13(4):e0194098. PMID: 29641532. Tung N et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. 2015 Jan 1;121(1):25-33. PMID: 25186627. Yurgelun MB et al. Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. J Clin Oncol. 2017 Apr 1;35(10):1086-1095. PMID: 28135145. (less)
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Likely benign
(Mar 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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CDK4-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004748634.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Likely benign
(Aug 08, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000669084.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
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Germline Functional Evidence
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 germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Integrated genomic profiling expands clinical options for patients with cancer. | Beaubier N | Nature biotechnology | 2019 | PMID: 31570899 |
Germline mutations in candidate predisposition genes in individuals with cutaneous melanoma and at least two independent additional primary cancers. | Pritchard AL | PloS one | 2018 | PMID: 29641532 |
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 |
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Text-mined citations for rs144890720 ...
HelpRecord last updated May 01, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.