NM_000077.5(CDKN2A):c.149A>C (p.Gln50Pro) AND Familial melanoma

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Aug 30, 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:: RCV001220072.8

Allele description [Variation Report for NM_000077.5(CDKN2A):c.149A>C (p.Gln50Pro)]

NM_000077.5(CDKN2A):c.149A>C (p.Gln50Pro)

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.149A>C (p.Gln50Pro)

HGVS:

NC_000009.12:g.21974679T>G
NG_007485.1:g.24813A>C
NM_000077.5:c.149A>CMANE SELECT
NM_001195132.2:c.149A>C
NM_001363763.2:c.-3-3471A>C
NM_058195.4:c.194-3471A>C
NM_058197.5:c.149A>C
NP_000068.1:p.Gln50Pro
NP_000068.1:p.Gln50Pro
NP_001182061.1:p.Gln50Pro
NP_478104.2:p.Gln50Pro
LRG_11t1:c.149A>C
LRG_11:g.24813A>C
LRG_11p1:p.Gln50Pro
NC_000009.11:g.21974678T>G
NM_000077.4:c.149A>C
p.Q50P

Protein change:

Q50P

Links:

dbSNP: rs587778189

NCBI 1000 Genomes Browser:

rs587778189

Molecular consequence:

NM_001363763.2:c.-3-3471A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_058195.4:c.194-3471A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000077.5:c.149A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195132.2:c.149A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_058197.5:c.149A>C - 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
SCV001392045	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Aug 30, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 11815963, 16234564, 16896043, 30967399, 14508519, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001392045

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Aug 30, 2023)

germline

clinical testing

PubMed (6)
[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

Phenotypic variation in eight extended CDKN2A germline mutation familial atypical multiple mole melanoma-pancreatic carcinoma-prone families: the familial atypical mole melanoma-pancreatic carcinoma syndrome.

Lynch HT, Brand RE, Hogg D, Deters CA, Fusaro RM, Lynch JF, Liu L, Knezetic J, Lassam NJ, Goggins M, Kern S.

Cancer. 2002 Jan 1;94(1):84-96.

PubMed [citation]

PMID:: 11815963

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

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001392045.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 50 of the CDKN2A (p16INK4a) protein (p.Gln50Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with melanoma (PMID: 11815963, 16234564, 16896043, 30967399). ClinVar contains an entry for this variant (Variation ID: 187713). 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. Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 14508519). Studies have shown that this missense change is associated with altered splicing resulting in multiple RNA products (PMID: 14508519). 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: Sep 29, 2024

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