NM_000077.5(CDKN2A):c.44G>A (p.Trp15Ter) AND Familial melanoma

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 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:: RCV000685369.9

Allele description [Variation Report for NM_000077.5(CDKN2A):c.44G>A (p.Trp15Ter)]

NM_000077.5(CDKN2A):c.44G>A (p.Trp15Ter)

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.44G>A (p.Trp15Ter)

HGVS:

NC_000009.12:g.21974784C>T
NG_007485.1:g.24708G>A
NM_000077.5:c.44G>AMANE SELECT
NM_001195132.2:c.44G>A
NM_001363763.2:c.-3-3576G>A
NM_058195.4:c.194-3576G>A
NM_058197.5:c.44G>A
NP_000068.1:p.Trp15Ter
NP_000068.1:p.Trp15Ter
NP_001182061.1:p.Trp15Ter
NP_478104.2:p.Trp15Ter
LRG_11t1:c.44G>A
LRG_11:g.24708G>A
LRG_11p1:p.Trp15Ter
NC_000009.11:g.21974783C>T
NM_000077.4:c.44G>A

Protein change:

W15*

Links:

dbSNP: rs876658556

NCBI 1000 Genomes Browser:

rs876658556

Molecular consequence:

NM_001363763.2:c.-3-3576G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_058195.4:c.194-3576G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000077.5:c.44G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001195132.2:c.44G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_058197.5:c.44G>A - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000812847	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 22, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 16905682, 8710906, 10398427, 12072543, 15146471, 28830827, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000812847

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 22, 2023)

germline

clinical testing

PubMed (7)
[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

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

Prevalence of germ-line mutations in p16, p19ARF, and CDK4 in familial melanoma: analysis of a clinic-based population.

FitzGerald MG, Harkin DP, Silva-Arrieta S, MacDonald DJ, Lucchina LC, Unsal H, O'Neill E, Koh J, Finkelstein DM, Isselbacher KJ, Sober AJ, Haber DA.

Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8541-5.

PubMed [citation]

PMID:: 8710906
PMCID:: PMC38708

See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000812847.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change creates a premature translational stop signal (p.Trp15*) in the CDKN2A (p16INK4a) gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDKN2A (p16INK4a) are known to be pathogenic (PMID: 15146471, 16905682). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with melanoma (PMID: 8710906, 10398427, 12072543, 15146471, 28830827). ClinVar contains an entry for this variant (Variation ID: 230421). For these reasons, this variant has been classified as Pathogenic.

#	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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