Submissions for variant NM_058195.4(CDKN2A):c.194-3653G>T

dbSNP: rs1800586

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160410	SCV000210943	pathogenic	not provided	2024-09-20	criteria provided, single submitter	clinical testing	Describes a nucleotide substitution 34 base pairs upstream of the ATG translational start site of the CDKN2A gene that creates an aberrant ATG translation initiation codon; Published functional studies demonstrate a damaging effect: decreases translation from the wild-type ATG and results in a truncated protein that significantly affects reporter activity (PMID: 9916806, 20093296); Nucleotide substitution has no predicted effect on splicing and is not conserved across species; This variant is associated with the following publications: (PMID: 26557774, 26775776, 19523171, 16896043, 25780468, 9916806, 20093296, 26581427, 26681309, 26099287, 12072543, 26681312, 16397522, 16905682, 15146471, 28495237, 29263814, 28830827, 30067863, 30117292, 30113427, 31567591, 33077847, 32482799, 34598035, 17713569, 29922827)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168189	SCV000218853	pathogenic	Familial melanoma	2024-01-20	criteria provided, single submitter	clinical testing	This variant occurs in a non-coding region of the CDKN2A (p16INK4a) gene. It does not change the encoded amino acid sequence of the CDKN2A (p16INK4a) protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individual(s) with familial melanoma (PMID: 9916806, 10738302, 16397522, 17713569, 18025365, 18337833, 19523171). It is commonly reported in individuals of British ancestry (PMID: 9916806, 10738302, 16397522, 17713569, 18025365, 18337833, 19523171). ClinVar contains an entry for this variant (Variation ID: 182414). Studies have shown that this variant alters CDKN2A (p16INK4a) gene expression (PMID: 9916806, 20093296). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000493169	SCV000581504	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-29	criteria provided, single submitter	clinical testing	The c.-34G>T pathogenic mutation is located in the 5' untranslated region (5'UTR) of the CDKN2A gene. This mutation results from a G to T substitution 34 nucleotides upstream from the first translated codon. This sequence alteration creates a potential AUG initiation codon at base -35 and translation initiation from this novel start site predicts a truncated protein with no homology to wild type (Liu L et al. Nat. Genet. 1999 Jan;21:128-32). Functional studies demonstrate that the c.-34G>T mutation severely reduces the reporter activity in every cell type tested (Bisio A et al. Hum. Mol. Genet. 2010 Apr;19:1479-91). This alteration was identified in an individual with at least 3 primary melanoma diagnoses (Li C et al. Melanoma Res. 2020 06;30:247-251). In addition, this alteration has been reported in numerous families with melanoma, pancreatic cancer, and/or atypical nevi, and has been shown to segregate with disease (Liu L et al. Nat. Genet. 1999 Jan;21:128-32; Berwick M et al. Cancer Epidemiol. Biomarkers Prev. 2006 Aug;15:1520-5; Florell SR et al. J. Invest. Dermatol. 2008 Aug;128:2122-5; Larre Borges A et al. Br. J. Dermatol. 2009 Sep;161:536-41; Harland M et al. Hered. Cancer Clin. Pract. 2014 Nov;12:20; Bruno W et al. J. Am. Acad. Dermatol. 2016 Feb;74:325-32; Puig S et al. Genet. Med. 2016 Jul;18:727-36; Taylor NJ et al. J. Invest. Dermatol. 2017 12;137(12):2606-2612; Brand R et al. Cancer. 2018 Sep;124(17):3520-3527). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Counsyl	RCV000576396	SCV000677822	pathogenic	Melanoma-pancreatic cancer syndrome	2017-05-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763194	SCV000893807	pathogenic	Melanoma-pancreatic cancer syndrome; Melanoma, cutaneous malignant, susceptibility to, 2; Melanoma and neural system tumor syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000576396	SCV001137788	pathogenic	Melanoma-pancreatic cancer syndrome	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000160410	SCV001246067	pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	CDKN2A: PP1:Strong, PM2, PS3:Moderate, PS4:Moderate
Color Diagnostics, LLC DBA Color Health	RCV000493169	SCV001343363	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-21	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 variant is located in the 5' untranslated region of the CDKN2A gene (P16INK4A). A functional study has shown that this variant creates a new translation initiation AUG codon, and translation initiation from this novel site results in a truncated protein, while blocking wild-type protein expression (PMID: 9916806). This variant has been reported in over thirty individuals affected with melanoma (PMID: 9916806, 16397522, 17713569, 18025365, 19523171, 25023876, 25780468, 26581427, 26681309, 26775776, 29263814, 31567591) and has been shown to segregate with melanoma and pancreatic cancer in four different families (PMID: 9916806). This variant has been identified in 6/146754 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160410	SCV001470489	pathogenic	not provided	2019-11-05	criteria provided, single submitter	clinical testing	The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one patient with expected phenotype for this gene. Low nucleotide conservation. Assessment of experimental evidence suggests this variant results in abnormal protein function. Very strong co-segregation with disease, and data include affected and unaffected individuals from multiple families.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000160410	SCV002010272	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002243829	SCV002512352	pathogenic	Ovarian neoplasm; Melanoma	2021-10-14	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PP1 strong
Baylor Genetics	RCV003474830	SCV004212478	pathogenic	Melanoma and neural system tumor syndrome	2024-01-31	criteria provided, single submitter	clinical testing
OMIM	RCV001762350	SCV000030245	risk factor	Melanoma, cutaneous malignant, susceptibility to, 2	1999-01-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004754323	SCV005362495	pathogenic	CDKN2A-related disorder	2024-09-17	no assertion criteria provided	clinical testing	The CDKN2A c.-34G>T variant is located in the 5' untranslated region. This variant corresponds to a deep intronic position in the alternate transcript for this gene that encodes p14ARF (NM_058195.3:c.194-3653G>T). This variant has been reported in individuals with melanoma and segregated within families (Liu et al. 1999. PubMed ID: 9916806; Harland et al. 2000. PubMed ID: 10738302; Andreotti et al. 2016. PubMed ID: 26581427). It has also been reported in an individual with pancreatic adenocarcinoma (Brand et al. 2018. PubMed ID: 30067863). In vitro experimental studies indicate that this variant results in a novel alternative initiator that subsequently leads to decreased translation from the normal start site and ultimately a truncated protein (Liu et al. 1999. PubMed ID: 9916806). In addition, this variant significantly alters transcriptional activity as observed by in vitro reporter assay (Bisio et al. 2010. PubMed ID: 20093296). This variant is reported in 6 of ~147,000 alleles in gnomAD; however, the data quality is questionable and should be interpreted with caution. This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/182414/). This variant is interpreted as pathogenic.