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NM_000077.5(CDKN2A):c.286G>C (p.Val96Leu) AND Familial melanoma

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Jan 25, 2021
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:
RCV001937024.6

Allele description [Variation Report for NM_000077.5(CDKN2A):c.286G>C (p.Val96Leu)]

NM_000077.5(CDKN2A):c.286G>C (p.Val96Leu)

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.286G>C (p.Val96Leu)
HGVS:
  • NC_000009.12:g.21971073C>G
  • NG_007485.1:g.28419G>C
  • NM_000077.5:c.286G>CMANE SELECT
  • NM_001195132.2:c.286G>C
  • NM_001363763.2:c.133G>C
  • NM_058195.4:c.329G>C
  • NM_058197.5:c.*209G>C
  • NP_000068.1:p.Val96Leu
  • NP_001182061.1:p.Val96Leu
  • NP_001350692.1:p.Val45Leu
  • NP_478102.2:p.Gly110Ala
  • LRG_11:g.28419G>C
  • NC_000009.11:g.21971072C>G
Protein change:
G110A
Links:
dbSNP: rs1587331506
NCBI 1000 Genomes Browser:
rs1587331506
Molecular consequence:
  • NM_058197.5:c.*209G>C - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_000077.5:c.286G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195132.2:c.286G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001363763.2:c.133G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_058195.4:c.329G>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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002225733Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Jan 25, 2021) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002225733.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts that have different open reading frames. 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest thatp.Val96Leuin p16INK4a is likely to be tolerated. These same algorithms are either unavailable or do not agree on the potential impact of p.Gly110Ala in p14ARF (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CDKN2A (p16INK4a)-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with leucine at codon 96 of the CDKN2A (p16INK4a) protein (p.Val96Leu). The valine residue is moderately conserved and there is a small physicochemical difference between valine and leucine. Alternatively, this sequence change replaces glycine with alanine at codon 110 of the CDKN2A (p14ARF) protein (p.Gly110Ala). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and alanine.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024