NM_000077.5(CDKN2A):c.95T>C (p.Leu32Pro) AND Familial melanoma

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Mar 10, 2021
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:: RCV000234305.10

Allele description [Variation Report for NM_000077.5(CDKN2A):c.95T>C (p.Leu32Pro)]

NM_000077.5(CDKN2A):c.95T>C (p.Leu32Pro)

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.95T>C (p.Leu32Pro)

HGVS:

NC_000009.12:g.21974733A>G
NG_007485.1:g.24759T>C
NM_000077.5:c.95T>CMANE SELECT
NM_001195132.2:c.95T>C
NM_001363763.2:c.-3-3525T>C
NM_058195.4:c.194-3525T>C
NM_058197.5:c.95T>C
NP_000068.1:p.Leu32Pro
NP_000068.1:p.Leu32Pro
NP_001182061.1:p.Leu32Pro
NP_478104.2:p.Leu32Pro
LRG_11t1:c.95T>C
LRG_11:g.24759T>C
LRG_11p1:p.Leu32Pro
NC_000009.11:g.21974732A>G
NM_000077.4:c.95T>C
P42771:p.Leu32Pro

Protein change:

L32P

Links:

UniProtKB: P42771#VAR_001416; dbSNP: rs878853650

NCBI 1000 Genomes Browser:

rs878853650

Molecular consequence:

NM_001363763.2:c.-3-3525T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_058195.4:c.194-3525T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000077.5:c.95T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195132.2:c.95T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_058197.5:c.95T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial melanoma
Synonyms:: Hereditary melanoma; Hereditary cutaneous melanoma
Identifiers:: MONDO: MONDO:0018961; MedGen: C1512419

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000283452	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Mar 10, 2021)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 19712690, 19759551, 17218939, 16905682, 20340136, 17047042, 28592523, 8595405, 28492532
SCV000917149	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 3, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 11500805, 20340136, 19759551 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000283452

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Mar 10, 2021)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV000917149

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Aug 3, 2018)

germline

clinical testing

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

Citations

PubMed

Functional impairment of p16(INK4A) due to CDKN2A p.Gly23Asp missense mutation.

Scaini MC, Rossi E, de Siqueira Torres PL, Zullato D, Callegaro M, Casella C, Quaggio M, Agata S, Malacrida S, Chiarion-Sileni V, Vecchiato A, Alaibac M, Montagna M, Mann GJ, Menin C, D'Andrea E.

Mutat Res. 2009 Dec 1;671(1-2):26-32. doi: 10.1016/j.mrfmmm.2009.08.007. Epub 2009 Aug 25.

PubMed [citation]

PMID:: 19712690

CDKN2A germline mutations in individuals with cutaneous malignant melanoma.

Orlow I, Begg CB, Cotignola J, Roy P, Hummer AJ, Clas BA, Mujumdar U, Canchola R, Armstrong BK, Kricker A, Marrett LD, Millikan RC, Gruber SB, Anton-Culver H, Zanetti R, Gallagher RP, Dwyer T, Rebbeck TR, Kanetsky PA, Wilcox H, Busam K, From L, et al.

J Invest Dermatol. 2007 May;127(5):1234-43. Epub 2007 Jan 11.

PubMed [citation]

PMID:: 17218939

See all PubMed Citations (10)

Details of each submission

From Invitae, SCV000283452.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic Experimental studies have shown that this missense change interferes with the interaction between p16INK4a and its binding partners CDK4 and CDK6 (PMID: 20340136, 19712690). This variant has been reported in patients and families affected with melanoma and pancreatic cancer (PMID: 19759551, 17218939, 16905682, 20340136, 17047042, 28592523). ¬†It has been shown to segregate with disease in one family (PMID: 8595405). ClinVar contains an entry for this variant (Variation ID: 236992). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 32 of the CDKN2A (p16INK4a) protein (p.Leu32Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917149.1

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

Description

Variant summary: CDKN2A c.95T>C (p.Leu32Pro) results in a non-conservative amino acid change located in the Ankyrin repeat-containing domain (IPR020683) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 239900 control chromosomes (gnomAD). The variant, c.95T>C, has been reported in the literature in individuals affected with Cutaneous Malignant Melanoma (Jouenne_2016, Jovanovic_2010, Box_2001, McKenzie_2010). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (McKenzie_2010). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	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: Apr 6, 2024

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