NM_000077.5(CDKN2A):c.146T>C (p.Ile49Thr) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Apr 1, 2024
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:: RCV000115331.27

Allele description [Variation Report for NM_000077.5(CDKN2A):c.146T>C (p.Ile49Thr)]

NM_000077.5(CDKN2A):c.146T>C (p.Ile49Thr)

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.146T>C (p.Ile49Thr)

Other names:

p.I49T:ATC>ACC

HGVS:

NC_000009.12:g.21974682A>G
NG_007485.1:g.24810T>C
NM_000077.5:c.146T>CMANE SELECT
NM_001195132.2:c.146T>C
NM_001363763.2:c.-3-3474T>C
NM_058195.4:c.194-3474T>C
NM_058197.5:c.146T>C
NP_000068.1:p.Ile49Thr
NP_000068.1:p.Ile49Thr
NP_001182061.1:p.Ile49Thr
NP_478104.2:p.Ile49Thr
LRG_11t1:c.146T>C
LRG_11:g.24810T>C
LRG_11p1:p.Ile49Thr
NC_000009.11:g.21974681A>G
NM_000077.4:c.146T>C
P42771:p.Ile49Thr
p.I49T

Protein change:

I49T

Links:

UniProtKB: P42771#VAR_001422; dbSNP: rs199907548

NCBI 1000 Genomes Browser:

rs199907548

Molecular consequence:

NM_001363763.2:c.-3-3474T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_058195.4:c.194-3474T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000077.5:c.146T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195132.2:c.146T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_058197.5:c.146T>C - 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
SCV000212740	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Apr 1, 2024)	germline	clinical testing	PubMed (19) [See all records that cite these PMIDs] 10389768, 10667595, 10719365, 15075790, 16234564, 21085193, 22440936, 25078331, 25980754, 26681309, 28454591, 30207590, 30339520, 31921681, 35001868, 7566978, 7647780, 7987387, 8573142 Citation Link,
SCV000910705	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 6, 2023)	germline	clinical testing	PubMed (18) [See all records that cite these PMIDs] 7566978, 7647780, 7987387, 8573142, 10389768, 10719365, 11687599, 15075790, 16234564, 16896043, 17218939, 18335566, 21085193, 21462282, 26681309, 33823155, 35001868, 25741868
SCV002534306	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Jan 24, 2022)	germline	curation	PubMed (14) [See all records that cite these PMIDs] 30207590, 26681309, 21462282, 18335566, 17218939, 7987387, 24733792, 28640387, 26670561, 32191290, 10389768, 35001868, 33823155, 7647780 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000212740

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Apr 1, 2024)

germline

clinical testing

PubMed (19)
[See all records that cite these PMIDs]

Citation Link,

SCV000910705

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 6, 2023)

germline

clinical testing

PubMed (18)
[See all records that cite these PMIDs]

SCV002534306

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Jan 24, 2022)

germline

curation

PubMed (14)
[See all records that cite these PMIDs]

Citation Link

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, curation

Citations

PubMed

Inherited predisposition to pancreatic adenocarcinoma: role of family history and germ-line p16, BRCA1, and BRCA2 mutations.

Lal G, Liu G, Schmocker B, Kaurah P, Ozcelik H, Narod SA, Redston M, Gallinger S.

Cancer Res. 2000 Jan 15;60(2):409-16.

PubMed [citation]

PMID:: 10667595

p16 gene mutations in Barrett's esophagus in gastric metaplasia - intestinal metaplasia - dysplasia - adenocarcinoma sequence.

Mokrowiecka A, Wierzchniewska-Ławska A, Smolarz B, Romanowicz-Makowska H, Małecka-Panas E.

Adv Med Sci. 2012 Jun 1;57(1):71-6. doi: 10.2478/v10039-012-0003-0.

PubMed [citation]

PMID:: 22440936

See all PubMed Citations (30)

Details of each submission

From Ambry Genetics, SCV000212740.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (19)

Description

The p.I49T variant (also known as c.146T>C), located in coding exon 1 of the CDKN2A gene, results from a T to C substitution at nucleotide position 146. The isoleucine at codon 49 is replaced by threonine, an amino acid with similar properties. This variant has been seen in multiple individuals with personal and/or family histories of pancreatic cancer (Ambry internal data). This variant has been reported in patients with no family history of melanoma but who had a single primary melanoma or multiple primary melanomas (Berwick M et al. Eur. J. Cancer Prev. 2004 Feb;13:65-70; Begg CB et al. J. Natl. Cancer Inst. 2005 Oct;97:1507-15). It has also been reported in multiple familial melanoma cases, however, in one case, it did not completely segregate with disease (Hussussian CJ et al. Nat. Genet. 1994 Sep;8:15-21; Puig S et al. Genet. Med. 2016 Jul;18:727-36). Multiple functional studies have demonstrated that this variant diminishes the binding activity of p16 to CDK4 and CDK6 and displays reduced ability to effect Rb dephosphorylation, however the degree of effect is shown to be more intermediate than other known pathogenic variants (Ranade K et al. Nat. Genet. 1995 May;10:114-6; Reymond A et al. Oncogene. 1995 Sep;11:1173-8; Yang R et al. Biochem. Biophys. Res. Commun. 1996 Jan;218:254-9; Walker GJ et al. Int. J. Cancer. 1999 Jul;82:305-12). Cell cycle inhibition assays have demonstrated that this variant is functionally deleterious (Miller, PJ et al. Hum Mutat 2011 Aug;32(8):900-11; Kimura H et al. Elife 2022 Jan;11:). Internal structural analysis predicts that this amino acid position is involved in CDK4 binding and while other pathogenic missense mutations are also found at this location, the substitution of threonine at this position induces a milder perturbation on the structure than those variants (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic with moderate risk.

#	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, SCV000910705.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (18)

Description

This variant replaces isoleucine with threonine at codon 49 of the CDKN2A (p16INK4A) protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported the mutant protein to be partially to fully functional in CDK4 and CDK6 binding in yeast and mammalian assays (PMID: 7566978, 7647780, 8573142, 10389768, 10719365, 21462282). Cell cycle and growth arrest assays have produced inconsistent results with the mutant protein showing normal activity (PMID: 33823155) or significantly reduced activity (PMID: 10389768, 21462282, 35001868). This variant has been reported in multiple individuals and families affected with melanoma (PMID: 7987387, 11687599, 15075790, 16234564, 16896043, 17218939, 18335566, 21085193, 21462282, 26681309). This variant has also been identified in 158/280824 chromosomes (157/35432 Latino chromosomes) by the Genome Aggregation Database (gnomAD). Although this variant has been observed in multiple individuals affected with melanoma, it occurs at a high allele frequency in the general population (0.44% in the Latino population). The available 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

From Sema4, Sema4, SCV002534306.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (14)

#	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: Oct 13, 2024

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