NM_000077.5(CDKN2A):c.407dup (p.Thr137fs) AND Familial melanoma

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 15, 2024
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:: RCV000690172.9

Allele description [Variation Report for NM_000077.5(CDKN2A):c.407dup (p.Thr137fs)]

NM_000077.5(CDKN2A):c.407dup (p.Thr137fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

9p21.3

Genomic location:

Preferred name:

NM_000077.5(CDKN2A):c.407dup (p.Thr137fs)

HGVS:

NC_000009.12:g.21970957dup
NG_007485.1:g.28540dup
NM_000077.5:c.407dupMANE SELECT
NM_001195132.2:c.407dup
NM_001363763.2:c.254dup
NM_058195.4:c.*51dup
NM_058197.5:c.*330dup
NP_000068.1:p.Thr137fs
NP_000068.1:p.Thr137fs
NP_001182061.1:p.Thr137fs
NP_001350692.1:p.Thr86fs
LRG_11t1:c.407dup
LRG_11:g.28540dup
LRG_11p1:p.Thr137fs
NC_000009.11:g.21970950_21970951insC
NC_000009.11:g.21970956dup
NM_000077.4:c.407dup
NM_000077.4:c.407dupG

Protein change:

T137fs

Links:

dbSNP: rs749588877

NCBI 1000 Genomes Browser:

rs749588877

Molecular consequence:

NM_058195.4:c.*51dup - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_058197.5:c.*330dup - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000077.5:c.407dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195132.2:c.407dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001363763.2:c.254dup - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000817851	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 15, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 19500876, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000817851

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 15, 2024)

germline

clinical testing

PubMed (2)
[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

Clinical genetic testing for familial melanoma in Italy: a cooperative study.

Bruno W, Ghiorzo P, Battistuzzi L, Ascierto PA, Barile M, Gargiulo S, Gensini F, Gliori S, Guida M, Lombardo M, Manoukian S, Menin C, Nasti S, Origone P, Pasini B, Pastorino L, Peissel B, Pizzichetta MA, Queirolo P, Rodolfo M, Romanini A, Scaini MC, et al.

J Am Acad Dermatol. 2009 Nov;61(5):775-82. doi: 10.1016/j.jaad.2009.03.039. Epub 2009 Jun 4.

PubMed [citation]

PMID:: 19500876

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000817851.7

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

Description

This sequence change creates a premature translational stop signal (p.Thr137Hisfs*5) in the CDKN2A (p16INK4a) gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 20 amino acid(s) of the CDKN2A (p16INK4a) protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with melanoma (PMID: 19500876). ClinVar contains an entry for this variant (Variation ID: 483327). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been 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

Last Updated: Oct 8, 2024

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