NM_000077.5(CDKN2A):c.265G>A (p.Gly89Ser) AND Familial melanoma

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 2, 2022
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:: RCV001305246.6

Allele description [Variation Report for NM_000077.5(CDKN2A):c.265G>A (p.Gly89Ser)]

NM_000077.5(CDKN2A):c.265G>A (p.Gly89Ser)

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.265G>A (p.Gly89Ser)

Other names:

G259S

HGVS:

NC_000009.12:g.21971094C>T
NG_007485.1:g.28398G>A
NM_000077.5:c.265G>AMANE SELECT
NM_001195132.2:c.265G>A
NM_001363763.2:c.112G>A
NM_058195.4:c.308G>A
NM_058197.5:c.*188G>A
NP_000068.1:p.Gly89Ser
NP_001182061.1:p.Gly89Ser
NP_001350692.1:p.Gly38Ser
NP_478102.2:p.Gly103Glu
LRG_11t1:c.265G>A
LRG_11:g.28398G>A
NC_000009.11:g.21971093C>T
NM_000077.4:c.265G>A
P42771:p.Gly89Ser

Protein change:

G103E; GLY259SER

Links:

UniProtKB: P42771#VAR_001454; OMIM: 600160.0001; dbSNP: rs137854597

NCBI 1000 Genomes Browser:

rs137854597

Molecular consequence:

NM_058197.5:c.*188G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000077.5:c.265G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195132.2:c.265G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001363763.2:c.112G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_058195.4:c.308G>A - 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
SCV001494575	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 2, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 8668202, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001494575

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 2, 2022)

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

Temperature-sensitive mutants of p16CDKN2 associated with familial melanoma.

Parry D, Peters G.

Mol Cell Biol. 1996 Jul;16(7):3844-52.

PubMed [citation]

PMID:: 8668202
PMCID:: PMC231381

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, SCV001494575.4

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

Description

This variant is also known as c.308G>A (p.Gly103Glu) in the CDKN2A (p14ARF) transcript. This variant has not been reported in the literature in individuals affected with CDKN2A (p16INK4a)-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 89 of the CDKN2A (p16INK4a) protein (p.Gly89Ser). 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. ClinVar contains an entry for this variant (Variation ID: 9408). 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. Experimental studies have shown that this missense change does not substantially affect CDKN2A (p16INK4a) function (PMID: 8668202). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive.

#	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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