NM_000077.5(CDKN2A):c.170C>A (p.Ala57Asp) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 27, 2023
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:: RCV000562625.11

Allele description [Variation Report for NM_000077.5(CDKN2A):c.170C>A (p.Ala57Asp)]

NM_000077.5(CDKN2A):c.170C>A (p.Ala57Asp)

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.170C>A (p.Ala57Asp)

HGVS:

NC_000009.12:g.21971189G>T
NG_007485.1:g.28303C>A
NM_000077.5:c.170C>AMANE SELECT
NM_001195132.2:c.170C>A
NM_001363763.2:c.17C>A
NM_058195.4:c.213C>A
NM_058197.5:c.*93C>A
NP_000068.1:p.Ala57Asp
NP_000068.1:p.Ala57Asp
NP_001182061.1:p.Ala57Asp
NP_001350692.1:p.Ala6Asp
NP_478102.2:p.Arg71=
LRG_11t1:c.170C>A
LRG_11:g.28303C>A
LRG_11p1:p.Ala57Asp
NC_000009.11:g.21971188G>T
NM_000077.3:c.170C>A
NM_000077.4:c.170C>A

Protein change:

A57D

Links:

dbSNP: rs372266620

NCBI 1000 Genomes Browser:

rs372266620

Molecular consequence:

NM_058197.5:c.*93C>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000077.5:c.170C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195132.2:c.170C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001363763.2:c.17C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_058195.4:c.213C>A - synonymous variant - [Sequence Ontology: SO:0001819]

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
SCV000669179	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jan 27, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000684513	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 7, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 29641532, 35029067, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000669179

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jan 27, 2023)

germline

clinical testing

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

Citation Link,

SCV000684513

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 7, 2022)

germline

clinical testing

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

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

Clinical and Molecular Assessment of Patients with Lynch Syndrome and Sarcomas Underpinning the Association with MSH2 Germline Pathogenic Variants.

de Angelis de Carvalho N, Niitsuma BN, Kozak VN, Costa FD, de Macedo MP, Kupper BEC, Silva MLG, Formiga MN, Volc SM, Aguiar Junior S, Palmero EI, Casali-da-Rocha JC, Carraro DM, Torrezan GT.

Cancers (Basel). 2020 Jul 9;12(7). doi:pii: E1848. 10.3390/cancers12071848.

PubMed [citation]

PMID:: 32659967
PMCID:: PMC7408879

Germline mutations in candidate predisposition genes in individuals with cutaneous melanoma and at least two independent additional primary cancers.

Pritchard AL, Johansson PA, Nathan V, Howlie M, Symmons J, Palmer JM, Hayward NK.

PLoS One. 2018;13(4):e0194098. doi: 10.1371/journal.pone.0194098.

PubMed [citation]

PMID:: 29641532
PMCID:: PMC5894988

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000669179.6

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

Description

The p.A57D variant (also known as c.170C>A), located in coding exon 2 of the CDKN2A gene, results from a C to A substitution at nucleotide position 170. The alanine at codon 57 is replaced by aspartic acid, an amino acid with dissimilar properties. This alteration was identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS ONE, 2018 Apr;13:e0194098). This alteration has also been reported in a cohort of patients with Lynch syndrome-associated tumors and a personal or family history of sarcoma (de Angelis de Carvalho N et al. Cancers (Basel), 2020 Jul;12:). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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, SCV000684513.5

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

Description

The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/). This missense variant replaces alanine with aspartic acid at codon 57 of the CDKN2A (p16INK4A) protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with early-onset rectal cancer (PMID: 35029067) and in an individual unaffected with cancer (PMID: 29641532). This variant has been identified in 2/220150 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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: Jun 23, 2024

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