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NM_000077.5(CDKN2A):c.198C>T (p.His66=) AND Hereditary cancer-predisposing syndrome

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Dec 21, 2023
Review status:
criteria provided, conflicting classifications
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:
RCV000570104.7

Allele description [Variation Report for NM_000077.5(CDKN2A):c.198C>T (p.His66=)]

NM_000077.5(CDKN2A):c.198C>T (p.His66=)

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.198C>T (p.His66=)
HGVS:
  • NC_000009.12:g.21971161G>A
  • NG_007485.1:g.28331C>T
  • NM_000077.5:c.198C>TMANE SELECT
  • NM_001195132.2:c.198C>T
  • NM_001363763.2:c.45C>T
  • NM_058195.4:c.241C>T
  • NM_058197.5:c.*121C>T
  • NP_000068.1:p.His66=
  • NP_000068.1:p.His66=
  • NP_001182061.1:p.His66=
  • NP_001350692.1:p.His15=
  • NP_478102.2:p.Arg81Trp
  • LRG_11t1:c.198C>T
  • LRG_11:g.28331C>T
  • LRG_11p1:p.His66=
  • NC_000009.11:g.21971160G>A
  • NM_000077.4:c.198C>T
Protein change:
R81W
Links:
dbSNP: rs374984975
NCBI 1000 Genomes Browser:
rs374984975
Molecular consequence:
  • NM_058197.5:c.*121C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_058195.4:c.241C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000077.5:c.198C>T - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_001195132.2:c.198C>T - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_001363763.2:c.45C>T - 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

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000664592Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Uncertain significance
(Dec 21, 2023) 		germlineclinical testing

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

Citation Link,

SCV000911543Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely benign
(May 25, 2017) 		germlineclinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

Germline CDKN2A mutations among Greek patients with early-onset and multiple primary cutaneous melanoma.

Stratigos AJ, Yang G, Dimisianos R, Nicolaou V, Stefanaki I, Katsambas AD, Tsao H.

J Invest Dermatol. 2006 Feb;126(2):399-401.

PubMed [citation]
PMID:
16374456

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, SCV000664592.5

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

Description

The c.198C>T variant (also known as p.H66H), located in coding exon 2 of the p16 isoform (NM_000077) of the CDKN2A gene, results from a C to T substitution at nucleotide position 198. This nucleotide substitution does not change the histidine at codon 66. This variant has been reported in an individual with early-onset melanoma (Stratigos AJ et al. J Invest Dermatol, 2006 Feb;126:399-401). This nucleotide position is not well conserved in available vertebrate species and in silico splice site analysis predicts that this alteration will not have any significant effect on splicing. However, this variant is also known as c.241C>T p.R81W in the p14 isoform (NM_058195) of CDKN2A, in which this variant results in a C to T substitution at nucleotide position 241, replacing the arginine at amino acid 81 with tryptophan, an amino acid with dissimilar properties. This amino acid is well conserved in this transcript. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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

From Color Diagnostics, LLC DBA Color Health, SCV000911543.1

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

Last Updated: Sep 29, 2024