NM_000077.5(CDKN2A):c.143C>G (p.Pro48Arg) AND Familial melanoma

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Mar 15, 2021
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:: RCV001857774.6

Allele description [Variation Report for NM_000077.5(CDKN2A):c.143C>G (p.Pro48Arg)]

NM_000077.5(CDKN2A):c.143C>G (p.Pro48Arg)

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.143C>G (p.Pro48Arg)

HGVS:

NC_000009.12:g.21974685G>C
NG_007485.1:g.24807C>G
NM_000077.5:c.143C>GMANE SELECT
NM_001195132.2:c.143C>G
NM_001363763.2:c.-3-3477C>G
NM_058195.4:c.194-3477C>G
NM_058197.5:c.143C>G
NP_000068.1:p.Pro48Arg
NP_000068.1:p.Pro48Arg
NP_001182061.1:p.Pro48Arg
NP_478104.2:p.Pro48Arg
LRG_11t1:c.143C>G
LRG_11:g.24807C>G
LRG_11p1:p.Pro48Arg
NC_000009.11:g.21974684G>C
NM_000077.4:c.143C>G

Protein change:

P48R

Links:

dbSNP: rs763804037

NCBI 1000 Genomes Browser:

rs763804037

Molecular consequence:

NM_001363763.2:c.-3-3477C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_058195.4:c.194-3477C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000077.5:c.143C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195132.2:c.143C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_058197.5:c.143C>G - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002120639	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Mar 15, 2021)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 11058911, 11556834, 17625456, 28830827, 29506128, 18714178, 21462282, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002120639

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Mar 15, 2021)

germline

clinical testing

PubMed (8)
[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

A novel germline mutation, P48T, in the CDKN2A/p16 gene in a patient with pancreatic carcinoma.

Moore PS, Zamboni G, Falconi M, Bassi C, Scarpa A.

Hum Mutat. 2000 Nov;16(5):447-8. No abstract available.

PubMed [citation]

PMID:: 11058911

CDKN2A and CDK4 mutation analysis in Italian melanoma-prone families: functional characterization of a novel CDKN2A germ line mutation.

Della Torre G, Pasini B, Frigerio S, Donghi R, Rovini D, Delia D, Peters G, Huot TJ, Bianchi-Scarra G, Lantieri F, Rodolfo M, Parmiani G, Pierotti MA.

Br J Cancer. 2001 Sep 14;85(6):836-44.

PubMed [citation]

PMID:: 11556834
PMCID:: PMC2375081

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002120639.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

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. This variant disrupts the p.Pro48 amino acid residue in CDKN2A (p16INK4a). Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11058911, 11556834, 17625456, 28830827). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with pancreatic cancer or melanoma (PMID: 29506128, 18714178, 21462282). ClinVar contains an entry for this variant (Variation ID: 231262). This variant is present in population databases (rs763804037, ExAC 0.01%). This sequence change replaces proline with arginine at codon 48 of the CDKN2A (p16INK4a) protein (p.Pro48Arg). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and arginine.

#	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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