NM_000077.5(CDKN2A):c.106del (p.Ala36fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Mar 5, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001524193.3

Allele description [Variation Report for NM_000077.5(CDKN2A):c.106del (p.Ala36fs)]

NM_000077.5(CDKN2A):c.106del (p.Ala36fs)

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.106del (p.Ala36fs)

HGVS:

NC_000009.12:g.21974726del
NG_007485.1:g.24770del
NM_000077.5:c.106delMANE SELECT
NM_001195132.2:c.106del
NM_001363763.2:c.-3-3514del
NM_058195.4:c.194-3514del
NM_058197.5:c.106del
NP_000068.1:p.Ala36fs
NP_001182061.1:p.Ala36fs
NP_478104.2:p.Ala36fs
LRG_11t1:c.106del
LRG_11:g.24770del
NC_000009.11:g.21974725del
NM_000077.4:c.106del
NM_000077.4:c.106delG

Protein change:

A36fs

Links:

dbSNP: rs398123152

NCBI 1000 Genomes Browser:

rs398123152

Molecular consequence:

NM_000077.5:c.106del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195132.2:c.106del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_058197.5:c.106del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001363763.2:c.-3-3514del - intron variant - [Sequence Ontology: SO:0001627]
NM_058195.4:c.194-3514del - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001733971	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 21, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005032100	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Mar 5, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22083977, 25064638, 26681309 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001733971

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Dec 21, 2020)

germline

clinical testing

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

SCV005032100

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Mar 5, 2024)

germline

clinical testing

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

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Novel germline CDKN2A mutation associated with head and neck squamous cell carcinomas and melanomas.

Cabanillas R, Astudillo A, Valle M, de la Rosa J, Álvarez R, Durán NS, Cadiñanos J.

Head Neck. 2013 Mar;35(3):E80-4. doi: 10.1002/hed.21911. Epub 2011 Nov 15.

PubMed [citation]

PMID:: 22083977

See all PubMed Citations (4)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001733971.1

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

Description

This variant deletes 1 nucleotide in exon 1 of the CDKN2A (p16INK4A) gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CDKN2A function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as 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

From Ambry Genetics, SCV005032100.1

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

Description

The c.106delG pathogenic mutation, located in coding exon 1 of the CDKN2A gene, results from a deletion of one nucleotide at nucleotide position 106, causing a translational frameshift with a predicted alternate stop codon (p.A36Rfs*17). This variant was identified in a family meeting clinical criteria for melanoma-pancreatic cancer syndrome. Specifically, the proband was affected with head and neck squamous cell carcinoma and cutaneous melanoma at 48 and 43 years old, respectively (Cabanillas R et al. Head Neck, 2013 Mar;35:E80-4). Multiple other affected individuals of Spanish ancestry have also tested positive for this mutation (Potrony M et al. J Am Acad Dermatol, 2014 Nov;71:888-95; Puig S et al. Genet Med, 2016 Jul;18:727-36). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

#	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 7, 2024

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