NM_000077.5(CDKN2A):c.67G>C (p.Gly23Arg) AND Familial melanoma

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 20, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001034206.6

Allele description [Variation Report for NM_000077.5(CDKN2A):c.67G>C (p.Gly23Arg)]

NM_000077.5(CDKN2A):c.67G>C (p.Gly23Arg)

Gene:

CDKN2A:cyclin dependent kinase inhibitor 2A [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9p21.3

Genomic location:

Preferred name:

NM_000077.5(CDKN2A):c.67G>C (p.Gly23Arg)

HGVS:

NC_000009.12:g.21974761C>G
NG_007485.1:g.24731G>C
NM_000077.5:c.67G>CMANE SELECT
NM_001195132.2:c.67G>C
NM_001363763.2:c.-3-3553G>C
NM_058195.4:c.194-3553G>C
NM_058197.5:c.67G>C
NP_000068.1:p.Gly23Arg
NP_000068.1:p.Gly23Arg
NP_001182061.1:p.Gly23Arg
NP_478104.2:p.Gly23Arg
LRG_11t1:c.67G>C
LRG_11t2:c.194-3553G>C
LRG_11:g.24731G>C
LRG_11p1:p.Gly23Arg
NC_000009.11:g.21974760C>G
NM_000077.4:c.67G>C
NM_058195.3:c.194-3553G>C

Protein change:

G23R

Links:

dbSNP: rs1131691186

NCBI 1000 Genomes Browser:

rs1131691186

Molecular consequence:

NM_001363763.2:c.-3-3553G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_058195.4:c.194-3553G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000077.5:c.67G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195132.2:c.67G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_058197.5:c.67G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial melanoma
Synonyms:: Hereditary melanoma; Hereditary cutaneous melanoma
Identifiers:: MONDO: MONDO:0018961; MedGen: C1512419

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HLA-DRB5 major histocompatibility complex, class II, DR beta 5 [Homo sapiens]
HLA-DRB5 major histocompatibility complex, class II, DR beta 5 [Homo sapiens]
Gene ID:3127

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001197537	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 20, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 9856841, 17167857, 24659262, 16234564, 26775776, 27267843, 28830827, 29661971, 32482799, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001197537

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 20, 2023)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

CDKN2a/p16INK4a mutations and lack of p19ARF involvement in familial melanoma kindreds.

Fargnoli MC, Chimenti S, Keller G, Soyer HP, Dal Pozzo V, Höfler H, Peris K.

J Invest Dermatol. 1998 Dec;111(6):1202-6.

PubMed [citation]

PMID:: 9856841

High prevalence of germline CDKN2A mutations in Slovenian cutaneous malignant melanoma families.

Hocevar M, Avbelj M, Perić B, Zgajnar J, Besić N, Battelino T.

Croat Med J. 2006 Dec;47(6):851-4.

PubMed [citation]

PMID:: 17167857
PMCID:: PMC2080476

See all PubMed Citations (10)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001197537.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly23 amino acid residue in CDKN2A (p16INK4a). Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9856841, 17167857). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 24659262). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 826633). This missense change has been observed in individual(s) with melanoma and/or pancreatic cancer (PMID: 16234564, 26775776, 27267843, 28830827, 29661971, 32482799; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 23 of the CDKN2A (p16INK4a) protein (p.Gly23Arg).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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