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NM_000077.5(CDKN2A):c.67G>C (p.Gly23Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Sep 22, 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:
RCV001025672.3

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:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001187910Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Sep 22, 2023) 		germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Lifetime risk of melanoma in CDKN2A mutation carriers in a population-based sample.

Begg CB, Orlow I, Hummer AJ, Armstrong BK, Kricker A, Marrett LD, Millikan RC, Gruber SB, Anton-Culver H, Zanetti R, Gallagher RP, Dwyer T, Rebbeck TR, Mitra N, Busam K, From L, Berwick M; Genes Environment and Melanoma Study Group..

J Natl Cancer Inst. 2005 Oct 19;97(20):1507-15.

PubMed [citation]
PMID:
16234564

Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents.

Goldstein AM, Chan M, Harland M, Hayward NK, Demenais F, Bishop DT, Azizi E, Bergman W, Bianchi-Scarra G, Bruno W, Calista D, Albright LA, Chaudru V, Chompret A, Cuellar F, Elder DE, Ghiorzo P, Gillanders EM, Gruis NA, Hansson J, Hogg D, Holland EA, et al.

J Med Genet. 2007 Feb;44(2):99-106. Epub 2006 Aug 11.

PubMed [citation]
PMID:
16905682
PMCID:
PMC2598064
See all PubMed Citations (8)

Details of each submission

From Ambry Genetics, SCV001187910.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

The p.G23R variant (also known as c.67G>C), located in coding exon 1 of the CDKN2A gene, results from a G to C substitution at nucleotide position 67. The glycine at codon 23 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in multiple individuals with personal and/or family history of melanoma (Begg CB et al. J. Natl. Cancer Inst., 2005 Oct;97:1507-15, Goldstein AM et al. J. Med. Genet., 2007 Feb;44:99-106; Orlow I et al. J. Invest. Dermatol., 2007 May;127:1234-43; Taylor NJ et al. J. Invest. Dermatol., 2017 12;137:2606-2612; Potjer TP et al. J. Med. Genet., 2018 Oct;55:661-668). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Russo AA et al. Nature, 1998 Sep;395:237-43). Another alteration at the same codon, p.G23S (c.67G>A), has been reported as an Italian founder mutation based on its location in a functionally important domain of the protein, segregation with disease, and haplotype analyses showing one common ancestral origin (Begg CB et al. J. Natl. Cancer Inst. 2005 Oct;97(20):1507-15; Gensini F et al. Melanoma Res. 2007 Dec;17(6):387-92). This amino acid position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024