VCV000619828.9 - ClinVar

NM_000077.5(CDKN2A):c.262G>C (p.Glu88Gln)

Germline

Classification

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.

(4)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000077.5(CDKN2A):c.262G>C (p.Glu88Gln)

Variation ID: 619828 Accession: VCV000619828.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9p21.3 9: 21971097 (GRCh38) [ NCBI UCSC ] 9: 21971096 (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	Mar 19, 2019	May 1, 2024	Jan 8, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000077.5:c.262G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000068.1:p.Glu88Gln	missense
NM_058195.4:c.305G>C MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_478102.2:p.Gly102Ala	missense
NM_001195132.2:c.262G>C	NP_001182061.1:p.Glu88Gln	missense
NM_001363763.2:c.109G>C	NP_001350692.1:p.Glu37Gln	missense
NM_058197.5:c.*185G>C		3 prime UTR
NC_000009.12:g.21971097C>G
NC_000009.11:g.21971096C>G
NG_007485.1:g.28395G>C
LRG_11:g.28395G>C
LRG_11t1:c.262G>C	LRG_11p1:p.Glu88Gln

... more HGVS ... less HGVS

Protein change

E88Q, G102A, E37Q

Other names

Canonical SPDI

NC_000009.12:21971096:C:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

dbSNP: rs121913384 VarSome

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
Gene	OMIM	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.
not provided	Uncertain significance (1)	criteria provided, single submitter	Mar 2, 2018	RCV000759747.2
Familial melanoma	Uncertain significance (1)	criteria provided, single submitter	Jun 2, 2023	RCV001302306.5
Hereditary cancer-predisposing syndrome	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jan 8, 2024	RCV002256493.3

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.
Uncertain significance (Mar 02, 2018)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000889277.2 First in ClinVar: Mar 19, 2019 Last updated: Jan 01, 2022
Uncertain significance (Feb 14, 2022)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002534323.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The CDKN2A c.262G>C (p.E88Q) variant has been reported in heterozygosity in at least one individual with melanoma; however, this patient also had at least one … (more) The CDKN2A c.262G>C (p.E88Q) variant has been reported in heterozygosity in at least one individual with melanoma; however, this patient also had at least one pathogenic variant in CDKN2A (PMID: 12950144). It was not observed in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org). The variant has been reported in ClinVar (Variation ID 619828). Functional studies have not been performed, and in silico predictions of the variant's effect on protein function are inconclusive. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)	Publications: PubMed (1) PubMed: 12950144
Uncertain significance (Jun 02, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial melanoma Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001491508.4 First in ClinVar: Mar 07, 2021 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 12950144 Comment: 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 … (more) 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. 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. ClinVar contains an entry for this variant (Variation ID: 619828). This variant is also known as c.305G>C (p.Gly102Ala) in the CDKN2A (p14ARF) transcript. This missense change has been observed in individual(s) with melanoma who also carries a pathogenic variant in CDKN2A (PMID: 12950144). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 88 of the CDKN2A (p16INK4a) protein (p.Glu88Gln). The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts with different open reading frames. Both transcripts have been analyzed. We report either the variant with the higher classification or default to the CDKN2A (p16INK4a) variant. This report therefore includes the details for the CDKN2A (p16INK4a) variant. (less)
Uncertain significance (Jan 08, 2024)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV005032159.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 12950144 Comment: The p.E88Q variant (also known as c.262G>C), located in coding exon 2 of the CDKN2A gene, results from a G to C substitution at nucleotide … (more) The p.E88Q variant (also known as c.262G>C), located in coding exon 2 of the CDKN2A gene, results from a G to C substitution at nucleotide position 262. The glutamic acid at codon 88 is replaced by glutamine, an amino acid with highly similar properties. This alteration was detected in a proband with melanoma as well as in an unaffected family member. The affected proband was also found to have a pathogenic frameshift mutation in the CDKN2A gene that was not present in the unaffected relative (Levanat S et al. Croat Med J, 2003 Aug;44:418-24). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)

Comment:

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. 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. ClinVar contains an entry for this variant (Variation ID: 619828). This variant is also known as c.305G>C (p.Gly102Ala) in the CDKN2A (p14ARF) transcript. This missense change has been observed in individual(s) with melanoma who also carries a pathogenic variant in CDKN2A (PMID: 12950144). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 88 of the CDKN2A (p16INK4a) protein (p.Glu88Gln). The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts with different open reading frames. Both transcripts have been analyzed. We report either the variant with the higher classification or default to the CDKN2A (p16INK4a) variant. This report therefore includes the details for the CDKN2A (p16INK4a) variant.

Comment:

The p.E88Q variant (also known as c.262G>C), located in coding exon 2 of the CDKN2A gene, results from a G to C substitution at nucleotide position 262. The glutamic acid at codon 88 is replaced by glutamine, an amino acid with highly similar properties. This alteration was detected in a proband with melanoma as well as in an unaffected family member. The affected proband was also found to have a pathogenic frameshift mutation in the CDKN2A gene that was not present in the unaffected relative (Levanat S et al. Croat Med J, 2003 Aug;44:418-24). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Alterations in CDKN2A locus as potential indicator of melanoma predisposition in relatives of non-familial melanoma cases.	Levanat S	Croatian medical journal	2003	PMID: 12950144

Text-mined citations for rs121913384 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000077.5(CDKN2A):c.262G>C (p.Glu88Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121913384 ...