NM_000077.5(CDKN2A):c.64C>T (p.Arg22Trp) AND Familial melanoma

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jun 5, 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:: RCV001034459.7

Allele description [Variation Report for NM_000077.5(CDKN2A):c.64C>T (p.Arg22Trp)]

NM_000077.5(CDKN2A):c.64C>T (p.Arg22Trp)

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.64C>T (p.Arg22Trp)

HGVS:

NC_000009.12:g.21974764G>A
NG_007485.1:g.24728C>T
NM_000077.5:c.64C>TMANE SELECT
NM_001195132.2:c.64C>T
NM_001363763.2:c.-3-3556C>T
NM_058195.4:c.194-3556C>T
NM_058197.5:c.64C>T
NP_000068.1:p.Arg22Trp
NP_001182061.1:p.Arg22Trp
NP_478104.2:p.Arg22Trp
LRG_11t1:c.64C>T
LRG_11t2:c.194-3556C>T
LRG_11:g.24728C>T
NC_000009.11:g.21974763G>A
NM_000077.4:c.64C>T
NM_058195.3:c.194-3556C>T

Protein change:

R22W

Links:

dbSNP: rs374921006

NCBI 1000 Genomes Browser:

rs374921006

Molecular consequence:

NM_001363763.2:c.-3-3556C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_058195.4:c.194-3556C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000077.5:c.64C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195132.2:c.64C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_058197.5:c.64C>T - 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
SCV001197815	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jun 5, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25787093, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001197815

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jun 5, 2023)

germline

clinical testing

PubMed (2)
[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 Germline BAP1, CDKN2A, and CDK4 Mutations in an Australian Population-Based Sample of Cutaneous Melanoma Cases.

Aoude LG, Gartside M, Johansson P, Palmer JM, Symmons J, Martin NG, Montgomery GW, Hayward NK.

Twin Res Hum Genet. 2015 Apr;18(2):126-33. doi: 10.1017/thg.2015.12. Epub 2015 Mar 19.

PubMed [citation]

PMID:: 25787093

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV001197815.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

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. 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. ClinVar contains an entry for this variant (Variation ID: 833936). This missense change has been observed in individual(s) with a personal and family history of cutaneous malignant melanoma (PMID: 25787093). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 22 of the CDKN2A (p16INK4a) protein (p.Arg22Trp).

#	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: May 1, 2024

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