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NM_000077.5(CDKN2A):c.266G>A (p.Gly89Asp) AND Hereditary cancer-predisposing syndrome

Germline classification:
Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:
May 4, 2023
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:
RCV000219725.15

Allele description [Variation Report for NM_000077.5(CDKN2A):c.266G>A (p.Gly89Asp)]

NM_000077.5(CDKN2A):c.266G>A (p.Gly89Asp)

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.266G>A (p.Gly89Asp)
HGVS:
  • NC_000009.12:g.21971093C>T
  • NG_007485.1:g.28399G>A
  • NM_000077.5:c.266G>AMANE SELECT
  • NM_001195132.2:c.266G>A
  • NM_001363763.2:c.113G>A
  • NM_058195.4:c.309G>A
  • NM_058197.5:c.*189G>A
  • NP_000068.1:p.Gly89Asp
  • NP_000068.1:p.Gly89Asp
  • NP_001182061.1:p.Gly89Asp
  • NP_001350692.1:p.Gly38Asp
  • NP_478102.2:p.Gly103=
  • LRG_11t1:c.266G>A
  • LRG_11:g.28399G>A
  • LRG_11p1:p.Gly89Asp
  • NC_000009.11:g.21971092C>T
  • NM_000077.4:c.266G>A
  • P42771:p.Gly89Asp
Protein change:
G38D; GLY89ASP
Links:
UniProtKB: P42771#VAR_001453; OMIM: 600160.0019; dbSNP: rs137854599
NCBI 1000 Genomes Browser:
rs137854599
Molecular consequence:
  • NM_058197.5:c.*189G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_000077.5:c.266G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195132.2:c.266G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001363763.2:c.113G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_058195.4:c.309G>A - synonymous variant - [Sequence Ontology: SO:0001819]

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000275864Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)
Likely pathogenic
(May 4, 2023)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV000906449Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Feb 27, 2023)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV002534324Sema4, Sema4
criteria provided, single submitter

(Sema4 Curation Guidelines)
Likely pathogenic
(Sep 12, 2021)
germlinecuration

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, curation

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

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
See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000275864.9

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

The p.G89D variant (also known as c.266G>A), located in coding exon 2 of the CDKN2A gene, results from a G to A substitution at nucleotide position 266. The glycine at codon 89 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been reported as a highly penetrant Icelandic founder mutation in the CDKN2A gene with a significantly increased risk of melanoma, head and neck cancers, and pancreatic cancer in carrier families (Goldstein AM et al. J Med Genet. 2008 May;45(5):284-9). In an in vitro cell proliferation assay, this alteration was classified as functionally deleterious (Kimura H et al. Elife, 2022 01;11). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Color Diagnostics, LLC DBA Color Health, SCV000906449.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/). This variant replaces glycine with aspartic acid at codon 89 of the CDKN2A (p16INK4A) protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant failed to suppress cell proliferation and showed cell cycle changes similar to known pathogenic variants (PMID: 35001868). This variant has been reported in multiple families and individuals affected with melanoma and/or pancreatic cancer (PMID: 18178632, 21462282, 33945383) and is reported to be associated with melanoma in a case-control study (PMID: 18178632). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Sema4, Sema4, SCV002534324.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024