NM_000077.4(CDKN2A):c.458-105A>G AND Hereditary cutaneous melanoma

This record was updated by the submitter. Please see the current version.

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 24, 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:: RCV000460188.1

Allele description

NM_000077.4(CDKN2A):c.458-105A>G

Gene:

CDKN2A:cyclin dependent kinase inhibitor 2A [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9p21.3

Genomic location:

Preferred name:

NM_000077.4(CDKN2A):c.458-105A>G

HGVS:

NC_000009.12:g.21968347T>C
NG_007485.1:g.31145A>G
NM_000077.4:c.458-105A>G
NM_058195.3:c.*102-105A>G
LRG_11t1:c.458-105A>G
LRG_11t2:c.*102-105A>G
LRG_11:g.31145A>G
NC_000009.11:g.21968346T>C

Links:

dbSNP: rs1060501266

NCBI 1000 Genomes Browser:

rs1060501266

Molecular consequence:

NM_000077.4:c.458-105A>G - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000545537	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 24, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000545537

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 24, 2016)

germline

clinical testing

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

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV000545537.2

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

Description

This sequence change falls in intron 2 of the CDKN2A gene. It does not directly change the encoded amino acid sequence of the CDKN2A protein. This variant is not present in population databases (1KG no frequency). This variant has been reported in multiple families with cutaneous melanoma (PMID: 16905682, 22841127), and has been shown to segregate with disease (PMID: 11726555). In one family, this variant arose de novo in an individual affected with eight primary melanomas (PMID: 15009729). This variant is also known as IVS2-105A>G in the literature. An experimental study has shown that this intronic change disrupts RNA splicing, leading to the inclusion of most or all of intron 2 in the CDKN2A mRNA. This is expected to disrupt the final four amino acids of the CDKN2A protein, encoded by exon 3 (PMID: 11726555). In summary, this is a rare intronic change that segregates with disease in multiple families. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely 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: May 12, 2018

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