NM_000077.5(CDKN2A):c.296G>C (p.Arg99Pro) AND Familial melanoma

This record was updated by the submitter. Please see the current version.

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Sep 8, 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:: RCV000687200.9

Allele description

NM_000077.5(CDKN2A):c.296G>C (p.Arg99Pro)

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.296G>C (p.Arg99Pro)

HGVS:

NC_000009.12:g.21971063C>G
NG_007485.1:g.28429G>C
NM_000077.5:c.296G>CMANE SELECT
NM_001195132.2:c.296G>C
NM_001363763.2:c.143G>C
NM_058195.4:c.339G>C
NM_058197.5:c.*219G>C
NP_000068.1:p.Arg99Pro
NP_000068.1:p.Arg99Pro
NP_001182061.1:p.Arg99Pro
NP_001350692.1:p.Arg48Pro
NP_478102.2:p.Pro113=
LRG_11t1:c.296G>C
LRG_11:g.28429G>C
LRG_11p1:p.Arg99Pro
NC_000009.11:g.21971062C>G
NM_000077.4:c.296G>C

Protein change:

R48P

Links:

dbSNP: rs754806883

NCBI 1000 Genomes Browser:

rs754806883

Molecular consequence:

NM_058197.5:c.*219G>C - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000077.5:c.296G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195132.2:c.296G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001363763.2:c.143G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_058195.4:c.339G>C - synonymous variant - [Sequence Ontology: SO:0001819]

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
SCV000814754	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Sep 8, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 9425228, 17047042, 21462282, 22841127, 24660985, 2319082, 19260062, 20340316, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000814754

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Sep 8, 2023)

germline

clinical testing

PubMed (9)
[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

Prevalence of p16 and CDK4 germline mutations in 48 melanoma-prone families in France. The French Familial Melanoma Study Group.

Soufir N, Avril MF, Chompret A, Demenais F, Bombled J, Spatz A, Stoppa-Lyonnet D, Bénard J, Bressac-de Paillerets B.

Hum Mol Genet. 1998 Feb;7(2):209-16. Erratum in: Hum Mol Genet 1998 May;7(5):941.

PubMed [citation]

PMID:: 9425228

High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL.

Goldstein AM, Chan M, Harland M, Gillanders EM, Hayward NK, Avril MF, Azizi E, Bianchi-Scarra G, Bishop DT, Bressac-de Paillerets B, Bruno W, Calista D, Cannon Albright LA, Demenais F, Elder DE, Ghiorzo P, Gruis NA, Hansson J, Hogg D, Holland EA, Kanetsky PA, Kefford RF, et al.

Cancer Res. 2006 Oct 15;66(20):9818-28.

PubMed [citation]

PMID:: 17047042

See all PubMed Citations (9)

Details of each submission

From Invitae, SCV000814754.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This variant is also known as c.339G>C in CDKN2A (p14ARF) transcript NM_058195.3. 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 replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 99 of the CDKN2A (p16INK4a) protein (p.Arg99Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with melanoma and/or pancreatic cancer (PMID: 9425228, 17047042, 19260062, 21462282, 22841127, 24660985). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 491572). Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 2319082, 19260062, 20340316). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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: Jul 23, 2024

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