NM_000077.5(CDKN2A):c.151-4G>C AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Dec 23, 2020
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:: RCV000130188.9

Allele description [Variation Report for NM_000077.5(CDKN2A):c.151-4G>C]

NM_000077.5(CDKN2A):c.151-4G>C

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.151-4G>C

HGVS:

NC_000009.12:g.21971212C>G
NG_007485.1:g.28280G>C
NM_000077.5:c.151-4G>CMANE SELECT
NM_001195132.2:c.151-4G>C
NM_001363763.2:c.-3-4G>C
NM_058195.4:c.194-4G>C
NM_058197.5:c.*74-4G>C
LRG_11t1:c.151-4G>C
LRG_11t2:c.194-4G>C
LRG_11:g.28280G>C
NC_000009.11:g.21971211C>G
NM_000077.4:c.151-4G>C
NM_058195.3:c.194-4G>C

Links:

dbSNP: rs529380972

NCBI 1000 Genomes Browser:

rs529380972

Molecular consequence:

NM_000077.5:c.151-4G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001195132.2:c.151-4G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001363763.2:c.-3-4G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_058195.4:c.194-4G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_058197.5:c.*74-4G>C - intron variant - [Sequence Ontology: SO:0001627]

Observations:

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
SCV000185025	Ambry Genetics	criteria provided, single submitter (Ambry Autosomal Dominant and X-Linked criteria (10/2015))	Uncertain significance (Mar 5, 2014)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000689586	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Jun 27, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002534311	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Benign (Dec 23, 2020)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000185025

Ambry Genetics

criteria provided, single submitter

(Ambry Autosomal Dominant and X-Linked criteria (10/2015))

Uncertain significance
(Mar 5, 2014)

germline

clinical testing

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

Citation Link,

SCV000689586

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Benign
(Jun 27, 2016)

germline

clinical testing

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

SCV002534311

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Benign
(Dec 23, 2020)

germline

curation

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	1	not provided	clinical testing, curation

Citations

PubMed

Germ-line mutations of the p16INK4(MTS1) gene occur in a subset of patients with hepatocellular carcinoma.

Chaubert P, Gayer R, Zimmermann A, Fontolliet C, Stamm B, Bosman F, Shaw P.

Hepatology. 1997 Jun;25(6):1376-81.

PubMed [citation]

PMID:: 9185756

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

Details of each submission

From Ambry Genetics, SCV000185025.6

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

Description

The c.194-4G>C intronic variant (also known as c.151-4G>C) results from a G to C substitution 4 nucleotides upstream from coding exon 2 in the CDKN2A gene. This alteration has been described in an individual diagnosed with early-onset hepatic carcinoma but hasn't been reported in melanoma cohorts to date (Chaubert P et al. Hepatology 1997; 25:1376-81). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. This nucleotide position is not well conserved in available vertebrate species. To date, this alteration has been detected with an allele frequency of approximately 0.16% (greater than 600 alleles tested) in our clinical cohort (includes this individual). Based on nucleotide sequence alignment, this position is well conserved in available vertebrate species.Using the BDGP and ESEfinder splice site prediction tools, this alteration does not have any significant effect on the native splice acceptor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of c.676-5T>C remains unclear.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	1	not provided	not provided		1	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV000689586.2

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

#	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 Sema4, Sema4, SCV002534311.1

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

#	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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