NM_000077.5(CDKN2A):c.104G>T (p.Gly35Val) AND Familial melanoma

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: May 12, 2016
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000474098.7

Allele description [Variation Report for NM_000077.5(CDKN2A):c.104G>T (p.Gly35Val)]

NM_000077.5(CDKN2A):c.104G>T (p.Gly35Val)

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.104G>T (p.Gly35Val)

HGVS:

NC_000009.12:g.21974724C>A
NG_007485.1:g.24768G>T
NM_000077.5:c.104G>TMANE SELECT
NM_001195132.2:c.104G>T
NM_001363763.2:c.-3-3516G>T
NM_058195.4:c.194-3516G>T
NM_058197.5:c.104G>T
NP_000068.1:p.Gly35Val
NP_000068.1:p.Gly35Val
NP_001182061.1:p.Gly35Val
NP_478104.2:p.Gly35Val
LRG_11t1:c.104G>T
LRG_11:g.24768G>T
LRG_11p1:p.Gly35Val
NC_000009.11:g.21974723C>A
NM_000077.4:c.104G>T

Protein change:

G35V

Links:

dbSNP: rs746834149

NCBI 1000 Genomes Browser:

rs746834149

Molecular consequence:

NM_001363763.2:c.-3-3516G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_058195.4:c.194-3516G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000077.5:c.104G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195132.2:c.104G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_058197.5:c.104G>T - 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
SCV000545530	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 12, 2016)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 24659262, 23190892, 19260062, 21462282, 22841127, 15937071, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000545530

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(May 12, 2016)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

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

CDKN2A unclassified variants in familial malignant melanoma: combining functional and computational approaches for their assessment.

Scaini MC, Minervini G, Elefanti L, Ghiorzo P, Pastorino L, Tognazzo S, Agata S, Quaggio M, Zullato D, Bianchi-Scarrà G, Montagna M, D'Andrea E, Menin C, Tosatto SC.

Hum Mutat. 2014 Jul;35(7):828-40. doi: 10.1002/humu.22550. Epub 2014 May 21.

PubMed [citation]

PMID:: 24659262

Familial melanoma-associated mutations in p16 uncouple its tumor-suppressor functions.

Jenkins NC, Jung J, Liu T, Wilde M, Holmen SL, Grossman D.

J Invest Dermatol. 2013 Apr;133(4):1043-51. doi: 10.1038/jid.2012.401. Epub 2012 Nov 29.

PubMed [citation]

PMID:: 23190892
PMCID:: PMC3594444

See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000545530.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This variant is not present in population databases (ExAC no frequency). Experimental studies in vitro have shown that this missense change impairs CDK4 binding and the ability of CDKN2A to inhibit proliferation of human diploid fibroblasts (PMID: 19260062, 24659262), but does not greatly differ from wild-type CDKN2A in its effect on cell cycle distribution or the generation of reactive oxygen species in a cell culture model (PMID: 23190892). This sequence change replaces glycine with valine at codon 35 of the CDKN2A protein (p.Gly35Val). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and valine. In summary, this variant is a rare missense change that has been observed in affected individuals and has been shown to impact some aspects of protein function in vitro. However, the evidence is insufficient to prove conclusively that this variant causes disease. For these reasons, this change has been classified as a Variant of Uncertain Significance. This variant has been reported in individuals affected with familial melanoma (PMID: 19260062, 21462282) and cutaneous melanoma (PMID: 22841127, 15937071).

#	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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