NM_000077.5(CDKN2A):c.58G>T (p.Ala20Ser) AND Familial melanoma

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 14, 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:: RCV000822590.7

Allele description [Variation Report for NM_000077.5(CDKN2A):c.58G>T (p.Ala20Ser)]

NM_000077.5(CDKN2A):c.58G>T (p.Ala20Ser)

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.58G>T (p.Ala20Ser)

HGVS:

NC_000009.12:g.21974770C>A
NG_007485.1:g.24722G>T
NM_000077.5:c.58G>TMANE SELECT
NM_001195132.2:c.58G>T
NM_001363763.2:c.-3-3562G>T
NM_058195.4:c.194-3562G>T
NM_058197.5:c.58G>T
NP_000068.1:p.Ala20Ser
NP_000068.1:p.Ala20Ser
NP_001182061.1:p.Ala20Ser
NP_478104.2:p.Ala20Ser
LRG_11t1:c.58G>T
LRG_11:g.24722G>T
LRG_11p1:p.Ala20Ser
NC_000009.11:g.21974769C>A
NM_000077.4:c.58G>T

Protein change:

A20S

Links:

dbSNP: rs760065045

NCBI 1000 Genomes Browser:

rs760065045

Molecular consequence:

NM_001363763.2:c.-3-3562G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_058195.4:c.194-3562G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000077.5:c.58G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195132.2:c.58G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_058197.5:c.58G>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
SCV000963399	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 14, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21462282, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000963399

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 14, 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

Classifying variants of CDKN2A using computational and laboratory studies.

Miller PJ, Duraisamy S, Newell JA, Chan PA, Tie MM, Rogers AE, Ankuda CK, von Walstrom GM, Bond JP, Greenblatt MS.

Hum Mutat. 2011 Aug;32(8):900-11. doi: 10.1002/humu.21504.

PubMed [citation]

PMID:: 21462282

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000963399.6

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

Description

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 20 of the CDKN2A (p16INK4a) protein (p.Ala20Ser). This variant is present in population databases (rs760065045, gnomAD 0.001%). This variant has not been reported in the literature in individuals affected with CDKN2A (p16INK4a)-related conditions. ClinVar contains an entry for this variant (Variation ID: 664488). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect CDKN2A (p16INK4a) function (PMID: 21462282). 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.

#	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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