NM_000077.5(CDKN2A):c.151-1G>C AND Familial melanoma

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 9, 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:: RCV001850264.6

Allele description [Variation Report for NM_000077.5(CDKN2A):c.151-1G>C]

NM_000077.5(CDKN2A):c.151-1G>C

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.151-1G>C

HGVS:

NC_000009.12:g.21971209C>G
NG_007485.1:g.28283G>C
NM_000077.5:c.151-1G>CMANE SELECT
NM_001195132.2:c.151-1G>C
NM_001363763.2:c.-3-1G>C
NM_058195.4:c.194-1G>C
NM_058197.5:c.*74-1G>C
LRG_11t1:c.151-1G>C
LRG_11:g.28283G>C
NC_000009.11:g.21971208C>G
NM_000077.4:c.151-1G>C

Links:

dbSNP: rs730881677

NCBI 1000 Genomes Browser:

rs730881677

Molecular consequence:

NM_000077.5:c.151-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001195132.2:c.151-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001363763.2:c.-3-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_058195.4:c.194-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_058197.5:c.*74-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

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

Recent activity

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cortactin-binding protein 2 [Nannochloropsis gaditana]
cortactin-binding protein 2 [Nannochloropsis gaditana]
gi|585104395|gb|EWM23384.1||gnl|WGS |Naga_101268g1.7023

Protein
uncharacterized protein SOCE26_016940 [Sorangium cellulosum]
uncharacterized protein SOCE26_016940 [Sorangium cellulosum]
gi|1338590150|gnl|PRJNA294368|SOCE2 940|gb|AUX40294.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002158387	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 9, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26876133, 11433531, 12920094, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002158387

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 9, 2023)

germline

clinical testing

PubMed (4)
[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 mutations with p14 loss predisposing to multiple nerve sheath tumours, melanoma, dysplastic naevi and internal malignancies: a case series and review of the literature.

Sargen MR, Merrill SL, Chu EY, Nathanson KL.

Br J Dermatol. 2016 Oct;175(4):785-9. doi: 10.1111/bjd.14485. Epub 2016 Jun 8. Review.

PubMed [citation]

PMID:: 26876133

CDKN2A germline splicing mutation affecting both p16(ink4) and p14(arf) RNA processing in a melanoma/neurofibroma kindred.

Petronzelli F, Sollima D, Coppola G, Martini-Neri ME, Neri G, Genuardi M.

Genes Chromosomes Cancer. 2001 Aug;31(4):398-401.

PubMed [citation]

PMID:: 11433531

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002158387.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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. This sequence change affects an acceptor splice site in intron 1 of the CDKN2A (p16INK4a) gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of melanoma-NST syndrome (PMID: 11433531, 12920094, 26876133). It has also been observed to segregate with disease in related individuals. This variant is also known as c.194-1G>C in CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 182416). Studies have shown that disruption of this splice site results in skipping of exon 2 and introduces a premature termination codon (PMID: 11433531, 12920094). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. The evidence indicates that this variant confers risk of developing CDKN2A (p16INK4a) and CDKN2A (p14ARF)-associated conditions.

#	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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