NM_000077.4(CDKN2A):c.434T>C (p.Ile145Thr) AND Hereditary melanoma

Clinical significance:Uncertain significance (Last evaluated: Oct 30, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:

Allele description [Variation Report for NM_000077.4(CDKN2A):c.434T>C (p.Ile145Thr)]

NM_000077.4(CDKN2A):c.434T>C (p.Ile145Thr)

CDKN2A:cyclin dependent kinase inhibitor 2A [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000077.4(CDKN2A):c.434T>C (p.Ile145Thr)
Other names:
  • NC_000009.12:g.21970925A>G
  • NG_007485.1:g.28567T>C
  • NM_000077.4:c.434T>C
  • NM_001195132.1:c.434T>C
  • NM_001363763.2:c.281T>C
  • NM_058195.3:c.*78T>C
  • NM_058197.4:c.*357T>C
  • NP_000068.1:p.Ile145Thr
  • NP_001182061.1:p.Ile145Thr
  • NP_001350692.1:p.Ile94Thr
  • LRG_11t1:c.434T>C
  • LRG_11t2:c.*78T>C
  • LRG_11:g.28567T>C
  • LRG_11p1:p.Ile145Thr
  • NC_000009.11:g.21970924A>G
Protein change:
dbSNP: rs730881680
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_058195.3:c.*78T>C - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_058197.4:c.*357T>C - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_000077.4:c.434T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195132.1:c.434T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001363763.2:c.281T>C - missense variant - [Sequence Ontology: SO:0001583]


Hereditary melanoma
Hereditary cutaneous melanoma; Familial melanoma
MONDO: MONDO:0018961; MedGen: C1512419

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000254245Invitaecriteria provided, single submitter
Uncertain significance
(Oct 30, 2020)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod



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):240-242.

PubMed [citation]

Details of each submission

From Invitae, SCV000254245.6

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


This sequence change replaces isoleucine with threonine at codon 145 of the CDKN2A (p16INK4a) protein (p.Ile145Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CDKN2A (p16INK4a)-related disease. ClinVar contains an entry for this variant (Variation ID: 182420). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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

Last Updated: Jun 18, 2021

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