NM_000077.5(CDKN2A):c.457+1_457+10del AND Familial melanoma

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Mar 5, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV001049532.10

Allele description [Variation Report for NM_000077.5(CDKN2A):c.457+1_457+10del]

NM_000077.5(CDKN2A):c.457+1_457+10del

Gene:

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

Variant type:

Deletion

Cytogenetic location:

9p21.3

Genomic location:

Preferred name:

NM_000077.5(CDKN2A):c.457+1_457+10del

HGVS:

NC_000009.12:g.21970892_21970901del
NC_000009.12:g.21970893_21970902del
NG_007485.1:g.28591_28600del
NM_000077.5:c.457+1_457+10delMANE SELECT
NM_001195132.2:c.457+1_457+10del
NM_001363763.2:c.304+1_304+10del
NM_058195.4:c.*101+1_*101+10del
NM_058197.5:c.*380+1_*380+10del
LRG_11t1:c.457+1_457+10del
LRG_11:g.28591_28600del
NC_000009.11:g.21970891_21970900del
NC_000009.11:g.21970892_21970901del
NM_000077.4:c.457+1_457+10del
NM_000077.4:c.457+1_457+10del10
NM_000077.5:c.457+1_457+10del10MANE SELECT

Links:

dbSNP: rs1587330284

NCBI 1000 Genomes Browser:

rs1587330284

Molecular consequence:

NM_000077.5:c.457+1_457+10del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195132.2:c.457+1_457+10del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001363763.2:c.304+1_304+10del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_058195.4:c.*101+1_*101+10del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_058197.5:c.*380+1_*380+10del - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV001213586	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 4, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17576681, 9536098, 28492532
SCV005040211	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Mar 5, 2024)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001213586

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 4, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV005040211

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Mar 5, 2024)

germline

clinical testing

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

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]

PMID:: 17576681
PMCID:: PMC1934990

Statistical features of human exons and their flanking regions.

Zhang MQ.

Hum Mol Genet. 1998 May;7(5):919-32.

PubMed [citation]

PMID:: 9536098

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001213586.5

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

Description

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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 825010). This variant has not been reported in the literature in individuals affected with CDKN2A (p16INK4a)-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a splice site in intron 2 of the CDKN2A (p16INK4a) gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product.

#	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, SCV005040211.2

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

Description

Variant summary: CDKN2A c.457+1_457+10del10 is located in a canonical splice-site in the penultimate exon and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. These predictions have yet to be confirmed by functional studies. However, skipping of exon 2 has been observed as a mechanism of disease for at least one CDKN2A variant located in the last nucleotide of exon 2, namely c.457G>T (p.Asp153Tyr) (Variation ID: 216035), supporting the functional relevance of the downstream region for protein function. The variant was absent in 245936 control chromosomes. To our knowledge, no occurrence of c.457+1_457+10del10 in individuals affected with Cutaneous Malignant Melanoma and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 825010). Based on the evidence outlined above, the variant was 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: Sep 29, 2024

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