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NM_000077.5(CDKN2A):c.149A>C (p.Gln50Pro) AND Hereditary cancer-predisposing syndrome

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Jan 10, 2024
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV000167463.4

Allele description [Variation Report for NM_000077.5(CDKN2A):c.149A>C (p.Gln50Pro)]

NM_000077.5(CDKN2A):c.149A>C (p.Gln50Pro)

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.149A>C (p.Gln50Pro)
HGVS:
  • NC_000009.12:g.21974679T>G
  • NG_007485.1:g.24813A>C
  • NM_000077.5:c.149A>CMANE SELECT
  • NM_001195132.2:c.149A>C
  • NM_001363763.2:c.-3-3471A>C
  • NM_058195.4:c.194-3471A>C
  • NM_058197.5:c.149A>C
  • NP_000068.1:p.Gln50Pro
  • NP_000068.1:p.Gln50Pro
  • NP_001182061.1:p.Gln50Pro
  • NP_478104.2:p.Gln50Pro
  • LRG_11t1:c.149A>C
  • LRG_11:g.24813A>C
  • LRG_11p1:p.Gln50Pro
  • NC_000009.11:g.21974678T>G
  • NM_000077.4:c.149A>C
  • p.Q50P
Protein change:
Q50P
Links:
dbSNP: rs587778189
NCBI 1000 Genomes Browser:
rs587778189
Molecular consequence:
  • NM_001363763.2:c.-3-3471A>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_058195.4:c.194-3471A>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000077.5:c.149A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195132.2:c.149A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_058197.5:c.149A>C - 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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000218319Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Jan 10, 2024) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

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

Germline splicing mutations of CDKN2A predispose to melanoma.

Loo JC, Liu L, Hao A, Gao L, Agatep R, Shennan M, Summers A, Goldstein AM, Tucker MA, Deters C, Fusaro R, Blazer K, Weitzel J, Lassam N, Lynch H, Hogg D.

Oncogene. 2003 Sep 25;22(41):6387-94.

PubMed [citation]
PMID:
14508519
See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000218319.8

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

The p.Q50P variant (also known as c.149A>C), located in coding exon 1 of the CDKN2A gene, results from an A to C substitution at nucleotide position 149. The glutamine at codon 50 is replaced by proline, an amino acid with similar properties. This alteration was initially reported in a melanoma and pancreatic cancer kindred. The proband was diagnosed with melanoma at age 29y and had three first-degree relatives (FDRs) with melanoma as well as one FDR and one second-degree relative (SDR) with pancreatic cancer (Lynch HT, Cancer 2002 Jan; 94(1):84-96). This alteration has also been reported in a proband with melanoma who had a family history of melanoma in 2/7 FDRs (Begg CB, J. Natl. Cancer Inst. 2005 Oct; 97(20):1507-15). RT-PCR of RNA extracted from lymphoblastoid cells showed an incomplete splicing impact for this alteration, predicted to result in a protein with an in-frame deletion of 23 amino acids (Loo JC, Oncogene 2003 Sep; 22(41):6387-94). In addition, a yeast-based assay reported that this alteration impaired binding with CDK4 (Loo JC, Oncogene 2003 Sep; 22(41):6387-94). Another alteration at the same codon, p.Q50R (c.149A>G), has been detected in melanoma and pancreatic cancer cohorts and was reported to segregate with melanoma in at least six melanoma-affected individuals in one family (Walker GJ et al. Hum. Mol. Genet. 1995 Oct;4:1845-52; Box NF et al. Am. J. Hum. Genet. 2001 Oct;69:765-73). This amino acid position is highly conserved in available vertebrate species. In addition, this missense alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 7, 2024