NM_000077.5(CDKN2A):c.457G>T (p.Asp153Tyr) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Sep 12, 2022
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:: RCV000223581.9

Allele description [Variation Report for NM_000077.5(CDKN2A):c.457G>T (p.Asp153Tyr)]

NM_000077.5(CDKN2A):c.457G>T (p.Asp153Tyr)

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.457G>T (p.Asp153Tyr)

HGVS:

NC_000009.12:g.21970902C>A
NG_007485.1:g.28590G>T
NM_000077.5:c.457G>TMANE SELECT
NM_001195132.2:c.457G>T
NM_001363763.2:c.304G>T
NM_058195.4:c.*101G>T
NM_058197.5:c.*380G>T
NP_000068.1:p.Asp153Tyr
NP_000068.1:p.Asp153Tyr
NP_001182061.1:p.Glu153Ter
NP_001350692.1:p.Asp102Tyr
LRG_11t1:c.457G>T
LRG_11:g.28590G>T
LRG_11p1:p.Asp153Tyr
NC_000009.11:g.21970901C>A
NM_000077.3:c.457G>T
NM_000077.4:c.457G>T

Protein change:

D102Y

Links:

dbSNP: rs45476696

NCBI 1000 Genomes Browser:

rs45476696

Molecular consequence:

NM_058195.4:c.*101G>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_058197.5:c.*380G>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000077.5:c.457G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001363763.2:c.304G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195132.2:c.457G>T - nonsense - [Sequence Ontology: SO:0001587]

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

Recent activity

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PREDICTED: Phascolarctos cinereus UTP23, small subunit processome component (UTP...
PREDICTED: Phascolarctos cinereus UTP23, small subunit processome component (UTP23), mRNA
gi|1190435337|ref|XM_020965436.1|

Nucleotide
Partial duplication of the proximal phalanx of the 3rd finger
Partial duplication of the proximal phalanx of the 3rd finger

MedGen
Complete duplication of the middle phalanges of the hand
Complete duplication of the middle phalanges of the hand

MedGen
Complete duplication of the middle phalanx of the 4th finger
Complete duplication of the middle phalanx of the 4th finger

MedGen
Complete duplication of the distal phalanx of the 2nd finger
Complete duplication of the distal phalanx of the 2nd finger

MedGen

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000274983	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Feb 28, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 10627132, 11815963, 12853981, 14508519, 16905682, 28726808 Citation Link,
SCV000684534	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 12, 2022)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 10627132, 11815963, 12853981, 14508519, 21150883, 24737347, 25356972, 28726808, 29922827, 25741868
SCV000695347	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 15, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24737347, 16905682 LabCorp Variant Classification Summary - May 2015.docx Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000274983

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Feb 28, 2022)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV000684534

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 12, 2022)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

SCV000695347

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Aug 15, 2017)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx

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

Novel germline p16(INK4) allele (Asp145Cys) in a family with multiple pancreatic carcinomas. Mutations in brief no. 148. Online.

Moskaluk CA, Hruban H, Lietman A, Smyrk T, Fusaro L, Fusaro R, Lynch J, Yeo CJ, Jackson CE, Lynch HT, Kern SE.

Hum Mutat. 1998;12(1):70.

PubMed [citation]

PMID:: 10627132

Phenotypic variation in eight extended CDKN2A germline mutation familial atypical multiple mole melanoma-pancreatic carcinoma-prone families: the familial atypical mole melanoma-pancreatic carcinoma syndrome.

Lynch HT, Brand RE, Hogg D, Deters CA, Fusaro RM, Lynch JF, Liu L, Knezetic J, Lassam NJ, Goggins M, Kern S.

Cancer. 2002 Jan 1;94(1):84-96.

PubMed [citation]

PMID:: 11815963

See all PubMed Citations (11)

Details of each submission

From Ambry Genetics, SCV000274983.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

The c.457G>T pathogenic mutation (also known as p.D153Y), located in coding exon 2 of the CDKN2A gene, results from a G to T substitution at nucleotide position 457. The amino acid change results in aspartic acid to tyrosine at codon 153, an amino acid with highly dissimilar properties. This change occurs in the last base pair of coding exon 2, which makes it likely to have some effect on normal mRNA splicing. This alteration has been identified in several kindreds with familial melanoma and/or pancreatic cancer (Ambry internal data; Moskaluk CA et al. Hum. Mutat. 1998;12(1):70; Lynch HT et al. Cancer. 2002 Jan;94(1):84-96; Rutter JL et al. Oncogene. 2003 Jul; 22(28):4444-8; Demenais F et al. J. Natl. Cancer Inst. 2010 Oct 20;102(20):1568-83; Lucas AL et al. Cancer. 2014 Jul;120(13):1960-7; Zhen DB et al. Genet. Med. 2015 Jul;17(7):569-77). RT-PCR splicing assays of mRNA from lymphocytes indicate that this alteration results in a transcript product from the splicing of a cryptic donor site located within exon 2, splicing out 74 base pairs encoded by exon 2, as well as a transcript with complete exon 2 skipping (Ambry internal data; Rutter JL et al. Oncogene. 2003 Jul; 22(28):4444-8; Loo JC et al. Oncogene. 2003 Sep;22(41):6387-94). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the available evidence, this alteration is classified as a pathogenic 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

From Color Diagnostics, LLC DBA Color Health, SCV000684534.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/ ). This missense variant replaces aspartic acid with tyrosine at codon 153 of the CDKN2A (p16INK4A) protein. RNA studies have shown that this variant causes the both the activation of a cryptic splice donor site within exon 2 resulting in the splicing out 74 bp, and the skipping of exon 2 (PMID: 12853981, 14508519). The predicted protein products lack either 24 amino acids encoded by exon 2 or all of exon 2, both causing a frameshift in exon 3. This variant also impacts the p14ARF transcript and protein, deleting 74 bp from the 3'UTR and skipping the entire exon 2. The consequences of the p14ARF deletions are not clear but may contribute to disease in carriers. This variant has been reported in numerous individuals affected with melanoma and pancreatic adenocarcinoma (PMID: 10627132, 11815963, 11815963, 12853981, 21150883, 24737347, 25356972, 28726808, 29922827). It has been shown that this variant segregates with disease in family studies (PMID: 11815963). 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000695347.1

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

Description

Variant summary: The CDKN2A c.457G>T (p.Asp153Tyr) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict damaging outcome for this variant (SNPsandGO and Mutation Taster not captured due to low reliability index and p-value, respectively). This variant leads to substitution of the last nucleotide in exon 2 and 5/5 splice prediction tools predict a significant impact on normal splicing. This variant is absent in 118670 control chromosomes from ExAC. This germline variant has been found in familial cases with cutaneous malignant melanoma and pancreatic cancer, including evidence of cosegregation with disease ((Lynch_2002, Loo_2003, Rutter_2003, McWilliams_2011, Lucas_2014). Functional studies have shown that this variant causes aberrant splicing in a similar manner with another splice-site variant c.457+1G>T. This variant leads to activation of a cryptic donor site located within exon 2, thus splicing out 74 bp encoded by exon 2. The predicted protein product of the mutant lacks 24 amino acids encoded by exon 2 and possesses a frameshift in exon 3 that yields six amino acids followed by a termination codon (Loo_2003, Rutter_2003). Multiple clinical diagnostic laboratories in ClinVar have classified this variant as pathogenic. Taken together, 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

Last Updated: Sep 29, 2024

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