NM_000077.5(CDKN2A):c.59C>G (p.Ala20Gly) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 26, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000562858.5

Allele description [Variation Report for NM_000077.5(CDKN2A):c.59C>G (p.Ala20Gly)]

NM_000077.5(CDKN2A):c.59C>G (p.Ala20Gly)

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.59C>G (p.Ala20Gly)

HGVS:

NC_000009.12:g.21974769G>C
NG_007485.1:g.24723C>G
NM_000077.5:c.59C>GMANE SELECT
NM_001195132.2:c.59C>G
NM_001363763.2:c.-3-3561C>G
NM_058195.4:c.194-3561C>G
NM_058197.5:c.59C>G
NP_000068.1:p.Ala20Gly
NP_000068.1:p.Ala20Gly
NP_001182061.1:p.Ala20Gly
NP_478104.2:p.Ala20Gly
LRG_11t1:c.59C>G
LRG_11:g.24723C>G
LRG_11p1:p.Ala20Gly
NC_000009.11:g.21974768G>C
NM_000077.4:c.59C>G

Protein change:

A20G

Links:

dbSNP: rs864622484

NCBI 1000 Genomes Browser:

rs864622484

Molecular consequence:

NM_001363763.2:c.-3-3561C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_058195.4:c.194-3561C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000077.5:c.59C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195132.2:c.59C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_058197.5:c.59C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000669171	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Apr 26, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV004361319	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 14, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 35001868, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000669171

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Apr 26, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV004361319

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 14, 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

Functional CDKN2A assay identifies frequent deleterious alleles misclassified as variants of uncertain significance.

Kimura H, Paranal RM, Nanda N, Wood LD, Eshleman JR, Hruban RH, Goggins MG, Klein AP; Familial Pancreatic Cancer Genome Sequencing Project., Roberts NJ.

Elife. 2022 Jan 10;11. doi:pii: e71137. 10.7554/eLife.71137.

PubMed [citation]

PMID:: 35001868
PMCID:: PMC8824478

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Ambry Genetics, SCV000669171.6

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

Description

The p.A20G variant (also known as c.59C>G), located in coding exon 1 of the CDKN2A gene, results from a C to G substitution at nucleotide position 59. The alanine at codon 20 is replaced by glycine, an amino acid with similar properties. A functional study reported this variant as potentially deleterious based on in-vitro assessment of impact on proliferation in human pancreatic cancer cell lines (Kimura H et al. Elife, 2022 Jan;11). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.

#	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

From Color Diagnostics, LLC DBA Color Health, SCV004361319.1

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

Description

The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/ ). This missense variant replaces alanine with glycine at codon 20 in the ankyrin repeat domain of the CDKN2A (p16INK4A) protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/231932 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Functional studies have reported that this variant causes a loss of CDKN2A (p16INK4A) function in cell proliferation assays and cell cycle analysis using CDKN2A-null cell lines (PMID: 35001868). Although there is a suspicion for a pathogenic role, the available clinical evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is 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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