NM_000077.5(CDKN2A):c.112C>T (p.Pro38Ser) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Apr 11, 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:: RCV001017393.9

Allele description [Variation Report for NM_000077.5(CDKN2A):c.112C>T (p.Pro38Ser)]

NM_000077.5(CDKN2A):c.112C>T (p.Pro38Ser)

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.112C>T (p.Pro38Ser)

HGVS:

NC_000009.12:g.21974716G>A
NG_007485.1:g.24776C>T
NM_000077.5:c.112C>TMANE SELECT
NM_001195132.2:c.112C>T
NM_001363763.2:c.-3-3508C>T
NM_058195.4:c.194-3508C>T
NM_058197.5:c.112C>T
NP_000068.1:p.Pro38Ser
NP_000068.1:p.Pro38Ser
NP_001182061.1:p.Pro38Ser
NP_478104.2:p.Pro38Ser
LRG_11t1:c.112C>T
LRG_11:g.24776C>T
LRG_11p1:p.Pro38Ser
NC_000009.11:g.21974715G>A
NM_000077.4:c.112C>T

Protein change:

P38S

Links:

dbSNP: rs1587339752

NCBI 1000 Genomes Browser:

rs1587339752

Molecular consequence:

NM_001363763.2:c.-3-3508C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_058195.4:c.194-3508C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000077.5:c.112C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195132.2:c.112C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_058197.5:c.112C>T - 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

Recent activity

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Rattus norvegicus gamma-aminobutyric acid type A receptor subunit beta 2 (Gabrb2...
Rattus norvegicus gamma-aminobutyric acid type A receptor subunit beta 2 (Gabrb2), transcript variant 1, mRNA
gi|2726160440|ref|NM_012957.3|

Nucleotide
Generalized hyperreflexia
Generalized hyperreflexia

MedGen

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001178468	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Apr 11, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17890059, 21462282 Citation Link,
SCV001344457	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 16, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002534303	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Mar 18, 2022)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 17890059, 21462282, 17047042 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001178468

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Apr 11, 2023)

germline

clinical testing

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

Citation Link,

SCV001344457

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 16, 2021)

germline

clinical testing

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

SCV002534303

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Mar 18, 2022)

germline

curation

PubMed (3)
[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

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

Germline CDKN2A/p16 mutations are rare in multiple primary and familial malignant melanoma in German patients.

Lukowsky A, Schäfer-Hesterberg G, Sterry W, Voit C.

J Dermatol Sci. 2008 Feb;49(2):163-5. Epub 2007 Sep 24. No abstract available.

PubMed [citation]

PMID:: 17890059

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV001178468.5

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

Description

The p.P38S variant (also known as c.112C>T), located in coding exon 1 of the CDKN2A gene, results from a C to T substitution at nucleotide position 112. The proline at codon 38 is replaced by serine, an amino acid with similar properties. This variant has been identified in an individual with multiple primary melanomas and was classified as a variant of uncertain significance using Bayesian method (Miller PJ et al. Hum Mutat, 2011 Aug;32:900-11). This variant was also identified in a German patient with multiple primary melanomas and was determined to be unlikely a polymorphism (Lukowsky A et al. J. Dermatol. Sci., 2008 Feb;49:163-5). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration 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, SCV001344457.2

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

Description

This missense variant replaces proline with serine at codon 38 of the CDKN2A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with multiple primary melanoma (PMID: 17890059). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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, SCV002534303.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (3)

#	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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