NM_000077.5(CDKN2A):c.122C>A (p.Pro41Gln) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Oct 2, 2023
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:: RCV000129476.12

Allele description [Variation Report for NM_000077.5(CDKN2A):c.122C>A (p.Pro41Gln)]

NM_000077.5(CDKN2A):c.122C>A (p.Pro41Gln)

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.122C>A (p.Pro41Gln)

HGVS:

NC_000009.12:g.21974706G>T
NG_007485.1:g.24786C>A
NM_000077.5:c.122C>AMANE SELECT
NM_001195132.2:c.122C>A
NM_001363763.2:c.-3-3498C>A
NM_058195.4:c.194-3498C>A
NM_058197.5:c.122C>A
NP_000068.1:p.Pro41Gln
NP_000068.1:p.Pro41Gln
NP_001182061.1:p.Pro41Gln
NP_478104.2:p.Pro41Gln
LRG_11t1:c.122C>A
LRG_11:g.24786C>A
LRG_11p1:p.Pro41Gln
NC_000009.11:g.21974705G>T
NM_000077.3:c.122C>A
NM_000077.4:c.122C>A
p.P41Q

Protein change:

P41Q

Links:

dbSNP: rs373407950

NCBI 1000 Genomes Browser:

rs373407950

Molecular consequence:

NM_001363763.2:c.-3-3498C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_058195.4:c.194-3498C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000077.5:c.122C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195132.2:c.122C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_058197.5:c.122C>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000184246	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Benign (Jan 27, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26104880, 30548481, 35001868 Citation Link,
SCV000684506	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 2, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 35001868, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000184246

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Benign
(Jan 27, 2023)

germline

clinical testing

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

Citation Link,

SCV000684506

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 2, 2023)

germline

clinical testing

PubMed (2)
[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

Inherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children.

Xu H, Zhang H, Yang W, Yadav R, Morrison AC, Qian M, Devidas M, Liu Y, Perez-Andreu V, Zhao X, Gastier-Foster JM, Lupo PJ, Neale G, Raetz E, Larsen E, Bowman WP, Carroll WL, Winick N, Williams R, Hansen T, Holm JC, Mardis E, et al.

Nat Commun. 2015 Jun 24;6:7553. doi: 10.1038/ncomms8553.

PubMed [citation]

PMID:: 26104880
PMCID:: PMC4544058

Germline mutations of renal cancer predisposition genes and clinical relevance in Chinese patients with sporadic, early-onset disease.

Wu J, Wang H, Ricketts CJ, Yang Y, Merino MJ, Zhang H, Shi G, Gan H, Linehan WM, Zhu Y, Ye D.

Cancer. 2019 Apr 1;125(7):1060-1069. doi: 10.1002/cncr.31908. Epub 2018 Dec 12.

PubMed [citation]

PMID:: 30548481
PMCID:: PMC8201926

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000184246.7

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

Description

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

#	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, SCV000684506.4

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

Description

This missense variant replaces proline with glutamine at codon 41 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). An experimental functional study has reported this variant was neutral in a cell proliferation assay (PMID: 35001868). This variant has not been reported in individuals affected with CDKN2A-related disorders in the literature. This variant has been identified in 9/276116 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: Sep 29, 2024

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