Submissions for variant NM_000077.5(CDKN2A):c.142C>A (p.Pro48Thr)

dbSNP: rs786204195

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168272	SCV000218944	pathogenic	Familial melanoma	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 48 of the CDKN2A (p16INK4a) protein (p.Pro48Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of familial atypical multiple mole melanoma syndrome (PMID: 11058911, 11556834, 17625456, 28830827). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 188286). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CDKN2A (p16INK4a) function (PMID: 11556834). This variant disrupts the p.Pro48 amino acid residue in CDKN2A (p16INK4a). Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9168184, 10338331, 10491434, 21462282). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001183314	SCV001349022	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-05-06	criteria provided, single submitter	clinical testing	The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/). This missense variant replaces proline with threonine at codon 48 of the CDKN2A (p16INK4A) protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown the mutant protein to exhibit normal ability to interact with CDK4 and CDK6 protein but show mildly impaired ability to control cell cycle (PMID: 11556834). This variant has been reported in over twenty individuals and families affected with melanoma (PMID: 11058911, 11556834, 11556834, 16470311, 17625456, 18299477, 18363633, 21672182, 21893440, 22841127, 25023876, 26775776, 30274933, 34664323). In one family, this variant segregated with melanoma in 6 of 12 carriers ; unaffected carriers in this family ranged in age from 23 to 50 years (PMID: 11556834). This variant has also been observed in an individual affected with pancreatic cancer with a first-degree relative also affected with pancreatic cancer (PMID: 11058911). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). While the variant impact on gene function is not clearly understood, the available clinical evidence indicate that this variant is associated with disease. Therefore, this variant is classified as Likely Pathogenic.
Ambry Genetics	RCV001183314	SCV002698486	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-10	criteria provided, single submitter	clinical testing	The p.P48T pathogenic mutation (also known as c.142C>A), located in coding exon 1 of the CDKN2A gene, results from a C to A substitution at nucleotide position 142. The proline at codon 48 is replaced by threonine, an amino acid with highly similar properties. This mutation was reported in a large Italian kindred with cutaneous melanoma, including a proband with multiple melanomas; p.P48T segregated with disease in 3 of 3 affected relatives tested (Della Torre G et al. Br J Cancer, 2001 Sep;85:836-44). This mutation has been identified in multiple Italian and Brazilian individuals with personal and family histories of cutaneous melanoma and/or pancreatic cancer (Moore PS et al. Hum Mutat, 2000 Nov;16:447-8; Foppiani L et al. Eur J Endocrinol, 2008 Mar;158:417-22; Menin C et al. Pigment Cell Melanoma Res, 2011 Aug;24:728-30; Bruno W et al. J Am Acad Dermatol, 2016 Feb;74:325-32; de &Aacute;vila AL et al. Fam Cancer, 2014 Dec;13:645-9; Puig S et al. Genet Med, 2016 07;18:727-36). One Hungarian patient with atypical mole syndrome and multiple primary melanomas diagnosed at age 30 was actually found to be homozygous for this mutation; his parents were confirmed heterozygous and remained unaffected in their 60s (Sz&eacute;ll M et al. Melanoma Res, 2007 Aug;17:251-4). Functional assays have been consistent in p.P48T showing normal CDK4 and CDK6 binding but abnormal cell cycle growth arrest (Della Torre G et al. Br J Cancer, 2001 Sep;85:836-44; Miller PJ et al. Hum Mutat, 2011 Aug;32:900-11). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Illumina Laboratory Services, Illumina	RCV001183314	SCV004801672	pathogenic	Hereditary cancer-predisposing syndrome	2020-04-09	criteria provided, single submitter	clinical testing	The CDKN2A c.142C>A p.(Pro48Thr) missense variant has been identified in multiple individuals and families with different cancer phenotypes (Moore et al. (2000); Della Torre et al. (2001); Széll et al. (2007; de Avila et al. (2014); Dalmasso et al. (2019)) This variant is not observed in version 2.1.1 of the Genome Aggregation Database. Functional studies by Della Torre et al. (2001) revealed that while the p.(Pro48Thr) variant did not affect binding to CDK4 or CDK6, the variant protein displayed a diminished ability to inhibit cell growth as compared to wild type when expressed in human fibroblasts. The authors also indicate that the variant may cause a defect in the arrest of the cell cycle. Moore et al. (2000) suggest that the p.(Pro48Thr) variant, which occurs in the first four-residue helix of the second ankyrin repeat, may alter the protein's structure or binding properties. Della Torre et al. (2001) note that this region of the protein is important for inhibitory activity. Two additional variants occurring at the same amino acid, p.(Pro48Leu) and p.(Pro48Arg), have been reported in individuals with cancer phenotypes (Platz et al. (1997); Debniak et al. 2008). Based on the collective evidence the c.142C>A p.(Pro48Thr) variant is classified as pathogenic for CDKN2A-related cancer susceptibility.