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.
ClinVar Genomic variation as it relates to human health
NM_000077.5(CDKN2A):c.151-4G>C
Germline
Classification
Help
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.
(12)
Help
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.
Conflicting classifications of pathogenicity
Uncertain significance(1); Benign(9); Likely benign(2)
Uncertain significance(1); Benign(9); Likely benign(2)
12
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000077.5(CDKN2A):c.151-4G>C
Variation ID: 141600 Accession: VCV000141600.34
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 9p21.3 9: 21971212 (GRCh38) [ NCBI UCSC ] 9: 21971211 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jan 6, 2017 Oct 20, 2024 Jan 30, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000077.5:c.151-4G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_058195.4:c.194-4G>C MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001195132.2:c.151-4G>C intron variant NM_001363763.2:c.-3-4G>C intron variant NM_058197.5:c.*74-4G>C intron variant NC_000009.12:g.21971212C>G NC_000009.11:g.21971211C>G NG_007485.1:g.28280G>C LRG_11:g.28280G>C LRG_11t1:c.151-4G>C LRG_11t2:c.194-4G>C - Protein change
- -
- Other names
- -
- Canonical SPDI
- NC_000009.12:21971211:C:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
0.00319 (G)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 30x 0.00328
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00200
Exome Aggregation Consortium (ExAC) 0.00278
1000 Genomes Project 0.00319
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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. |
|||
| CDKN2A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1261 | 1413 | |
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
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Dec 23, 2020 | RCV000130188.9 | |
| Benign (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 15, 2023 | RCV000431130.8 | |
| Benign (1) |
criteria provided, single submitter
|
Jan 30, 2024 | RCV000467989.12 | |
| Likely benign (2) |
criteria provided, multiple submitters, no conflicts
|
Apr 20, 2023 | RCV000410358.4 | |
| Benign (2) |
criteria provided, multiple submitters, no conflicts
|
Jul 1, 2023 | RCV000585904.12 | |
| Benign (1) |
criteria provided, single submitter
|
- | RCV001258294.3 |
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. |
|
|---|---|---|---|---|---|
|
Benign
(Jan 10, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000517091.4
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
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 … (more)
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. (less)
|
|
|
Uncertain significance
(Mar 05, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000185025.6
First in ClinVar: Aug 06, 2014 Last updated: Feb 19, 2018 |
Comment:
The c.194-4G>C intronic variant (also known as c.151-4G>C) results from a G to C substitution 4 nucleotides upstream from coding exon 2 in the CDKN2A … (more)
The c.194-4G>C intronic variant (also known as c.151-4G>C) results from a G to C substitution 4 nucleotides upstream from coding exon 2 in the CDKN2A gene. This alteration has been described in an individual diagnosed with early-onset hepatic carcinoma but hasn't been reported in melanoma cohorts to date (Chaubert P et al. Hepatology 1997; 25:1376-81). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. This nucleotide position is not well conserved in available vertebrate species. To date, this alteration has been detected with an allele frequency of approximately 0.16% (greater than 600 alleles tested) in our clinical cohort (includes this individual). Based on nucleotide sequence alignment, this position is well conserved in available vertebrate species.Using the BDGP and ESEfinder splice site prediction tools, this alteration does not have any significant effect on the native splice acceptor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of c.676-5T>C remains unclear. (less)
Number of individuals with the variant: 1
|
|
|
Benign
(Jul 31, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601017.3
First in ClinVar: Mar 08, 2017 Last updated: Dec 31, 2022 |
|
|
|
Likely benign
(Apr 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Melanoma-pancreatic cancer syndrome
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004018568.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing.
|
|
|
Benign
(Aug 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002550363.4
First in ClinVar: Jul 27, 2022 Last updated: Aug 18, 2023 |
|
|
|
Benign
(Jan 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial melanoma
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000557471.8
First in ClinVar: Apr 17, 2017 Last updated: Feb 14, 2024 |
|
|
|
Benign
(Jun 05, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695334.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The CDKN2A c.151-4G>C variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. … (more)
Variant summary: The CDKN2A c.151-4G>C variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. One functional study found that this variant does not affect splicing (Loo_Oncogene_2003). The variant of interest has been found in a large, broad control population, ExAC in 224/82416 control chromosomes (2 homozygotes) at a frequency of 0.0027179, which is approximately 9 times the estimated maximal expected allele frequency of a pathogenic CDKN2A variant (0.0003), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases recently classified this variant as likely benign/benign. Taken together, this variant is classified as benign. (less)
|
|
|
Benign
(-)
|
criteria provided, single submitter
Method: research
|
Hepatocellular carcinoma
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001435228.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
The heterozygous c.151-4G>C variant in CDKN2A has been identified in an individual with hepatocellular carcinoma (PMID: 9185756), but has also been identified in >1% of … (more)
The heterozygous c.151-4G>C variant in CDKN2A has been identified in an individual with hepatocellular carcinoma (PMID: 9185756), but has also been identified in >1% of South Asian chromosomes and 2 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal dominant hepatocellular carcinoma. (less)
|
|
|
Benign
(Dec 23, 2020)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002534311.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
|
|
|
Benign
(Jun 27, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000689586.2
First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022 |
|
|
|
Likely benign
(Aug 16, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Melanoma-pancreatic cancer syndrome
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000489089.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
|
|
|
Benign
(Jul 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004157610.10
First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024 |
Comment:
CDKN2A: BP4, BS1, BS2
Number of individuals with the variant: 1
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
The c.194-4G>C intronic variant (also known as c.151-4G>C) results from a G to C substitution 4 nucleotides upstream from coding exon 2 in the CDKN2A gene. This alteration has been described in an individual diagnosed with early-onset hepatic carcinoma but hasn't been reported in melanoma cohorts to date (Chaubert P et al. Hepatology 1997; 25:1376-81). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. This nucleotide position is not well conserved in available vertebrate species. To date, this alteration has been detected with an allele frequency of approximately 0.16% (greater than 600 alleles tested) in our clinical cohort (includes this individual). Based on nucleotide sequence alignment, this position is well conserved in available vertebrate species.Using the BDGP and ESEfinder splice site prediction tools, this alteration does not have any significant effect on the native splice acceptor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of c.676-5T>C remains unclear.
Comment:
This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing.
Comment:
Variant summary: The CDKN2A c.151-4G>C variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. One functional study found that this variant does not affect splicing (Loo_Oncogene_2003). The variant of interest has been found in a large, broad control population, ExAC in 224/82416 control chromosomes (2 homozygotes) at a frequency of 0.0027179, which is approximately 9 times the estimated maximal expected allele frequency of a pathogenic CDKN2A variant (0.0003), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases recently classified this variant as likely benign/benign. Taken together, this variant is classified as benign.
Comment:
The heterozygous c.151-4G>C variant in CDKN2A has been identified in an individual with hepatocellular carcinoma (PMID: 9185756), but has also been identified in >1% of South Asian chromosomes and 2 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal dominant hepatocellular carcinoma.
Comment:
CDKN2A: BP4, BS1, BS2
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. |
Comment:
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.
Comment:
The c.194-4G>C intronic variant (also known as c.151-4G>C) results from a G to C substitution 4 nucleotides upstream from coding exon 2 in the CDKN2A gene. This alteration has been described in an individual diagnosed with early-onset hepatic carcinoma but hasn't been reported in melanoma cohorts to date (Chaubert P et al. Hepatology 1997; 25:1376-81). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. This nucleotide position is not well conserved in available vertebrate species. To date, this alteration has been detected with an allele frequency of approximately 0.16% (greater than 600 alleles tested) in our clinical cohort (includes this individual). Based on nucleotide sequence alignment, this position is well conserved in available vertebrate species.Using the BDGP and ESEfinder splice site prediction tools, this alteration does not have any significant effect on the native splice acceptor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of c.676-5T>C remains unclear.
Comment:
This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing.
Comment:
Variant summary: The CDKN2A c.151-4G>C variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. One functional study found that this variant does not affect splicing (Loo_Oncogene_2003). The variant of interest has been found in a large, broad control population, ExAC in 224/82416 control chromosomes (2 homozygotes) at a frequency of 0.0027179, which is approximately 9 times the estimated maximal expected allele frequency of a pathogenic CDKN2A variant (0.0003), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases recently classified this variant as likely benign/benign. Taken together, this variant is classified as benign.
Comment:
The heterozygous c.151-4G>C variant in CDKN2A has been identified in an individual with hepatocellular carcinoma (PMID: 9185756), but has also been identified in >1% of South Asian chromosomes and 2 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal dominant hepatocellular carcinoma.
Comment:
CDKN2A: BP4, BS1, BS2
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Novel CDKN2A mutations in Austrian melanoma patients. | Burgstaller-Muehlbacher S | Melanoma research | 2015 | PMID: 26225579 |
| Prevalence and predictors of germline CDKN2A mutations for melanoma cases from Australia, Spain and the United Kingdom. | Harland M | Hereditary cancer in clinical practice | 2014 | PMID: 25780468 |
| Germline splicing mutations of CDKN2A predispose to melanoma. | Loo JC | Oncogene | 2003 | PMID: 14508519 |
| Germ-line mutations of the p16INK4(MTS1) gene occur in a subset of patients with hepatocellular carcinoma. | Chaubert P | Hepatology (Baltimore, Md.) | 1997 | PMID: 9185756 |
Text-mined citations for rs529380972 ...
HelpThese 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 Oct 20, 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.