ClinVar Miner

Submissions for variant NM_000077.5(CDKN2A):c.457G>T (p.Asp153Tyr)

dbSNP: rs45476696
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000198192 SCV000253763 pathogenic Familial melanoma 2023-12-26 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 153 of the CDKN2A (p16INK4a) protein (p.Asp153Tyr). RNA analysis indicates that this missense change induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with melanoma and pancreatic cancer (PMID: 10627132, 12853981, 14508519, 16905682, 20539244, 20876876, 21150883, 25356972; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 216035). 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 tolerated. Studies have shown that this missense change results in partial exon exclusion and introduces a new termination codon (PMID: 12853981, 14508519). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000223581 SCV000274983 pathogenic Hereditary cancer-predisposing syndrome 2022-02-28 criteria provided, single submitter clinical testing The c.457G>T pathogenic mutation (also known as p.D153Y), located in coding exon 2 of the CDKN2A gene, results from a G to T substitution at nucleotide position 457. The amino acid change results in aspartic acid to tyrosine at codon 153, an amino acid with highly dissimilar properties. This change occurs in the last base pair of coding exon 2, which makes it likely to have some effect on normal mRNA splicing. This alteration has been identified in several kindreds with familial melanoma and/or pancreatic cancer (Ambry internal data; Moskaluk CA et al. Hum. Mutat. 1998;12(1):70; Lynch HT et al. Cancer. 2002 Jan;94(1):84-96; Rutter JL et al. Oncogene. 2003 Jul; 22(28):4444-8; Demenais F et al. J. Natl. Cancer Inst. 2010 Oct 20;102(20):1568-83; Lucas AL et al. Cancer. 2014 Jul;120(13):1960-7; Zhen DB et al. Genet. Med. 2015 Jul;17(7):569-77). RT-PCR splicing assays of mRNA from lymphocytes indicate that this alteration results in a transcript product from the splicing of a cryptic donor site located within exon 2, splicing out 74 base pairs encoded by exon 2, as well as a transcript with complete exon 2 skipping (Ambry internal data; Rutter JL et al. Oncogene. 2003 Jul; 22(28):4444-8; Loo JC et al. Oncogene. 2003 Sep;22(41):6387-94). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the available evidence, this alteration is classified as a pathogenic mutation.
Counsyl RCV000576665 SCV000677826 likely pathogenic Melanoma-pancreatic cancer syndrome 2017-02-08 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000223581 SCV000684534 pathogenic Hereditary cancer-predisposing syndrome 2022-09-12 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 aspartic acid with tyrosine at codon 153 of the CDKN2A (p16INK4A) protein. RNA studies have shown that this variant causes the both the activation of a cryptic splice donor site within exon 2 resulting in the splicing out 74 bp, and the skipping of exon 2 (PMID: 12853981, 14508519). The predicted protein products lack either 24 amino acids encoded by exon 2 or all of exon 2, both causing a frameshift in exon 3. This variant also impacts the p14ARF transcript and protein, deleting 74 bp from the 3'UTR and skipping the entire exon 2. The consequences of the p14ARF deletions are not clear but may contribute to disease in carriers. This variant has been reported in numerous individuals affected with melanoma and pancreatic adenocarcinoma (PMID: 10627132, 11815963, 11815963, 12853981, 21150883, 24737347, 25356972, 28726808, 29922827). It has been shown that this variant segregates with disease in family studies (PMID: 11815963). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CDKN2A function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000223581 SCV000695347 pathogenic Hereditary cancer-predisposing syndrome 2017-08-15 criteria provided, single submitter clinical testing Variant summary: The CDKN2A c.457G>T (p.Asp153Tyr) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict damaging outcome for this variant (SNPsandGO and Mutation Taster not captured due to low reliability index and p-value, respectively). This variant leads to substitution of the last nucleotide in exon 2 and 5/5 splice prediction tools predict a significant impact on normal splicing. This variant is absent in 118670 control chromosomes from ExAC. This germline variant has been found in familial cases with cutaneous malignant melanoma and pancreatic cancer, including evidence of cosegregation with disease ((Lynch_2002, Loo_2003, Rutter_2003, McWilliams_2011, Lucas_2014). Functional studies have shown that this variant causes aberrant splicing in a similar manner with another splice-site variant c.457+1G>T. This variant leads to activation of a cryptic donor site located within exon 2, thus splicing out 74 bp encoded by exon 2. The predicted protein product of the mutant lacks 24 amino acids encoded by exon 2 and possesses a frameshift in exon 3 that yields six amino acids followed by a termination codon (Loo_2003, Rutter_2003). Multiple clinical diagnostic laboratories in ClinVar have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Myriad Genetics, Inc. RCV000576665 SCV004018551 likely pathogenic Melanoma-pancreatic cancer syndrome 2023-04-20 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 12853981]. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 12853981].
Baylor Genetics RCV003474952 SCV004212526 pathogenic Melanoma and neural system tumor syndrome 2022-09-11 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV003477665 SCV004221644 pathogenic not provided 2023-01-19 criteria provided, single submitter clinical testing This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with melanoma (PMID: 12853981 (2003), 14508519 (2003), 16905682 (2007), 20539244 (2010), 20876876 (2010), 21150883 (2011), 29263814 (2016), 34028844 (2021)), and individuals with pancreatic cancer (PMID: 21150883 (2011), 25356972 (2015), 28726808 (2018), 29263814 (2016), 29922827 (2018)). Functional splicing assays demonstrate this variant causes aberrant splicing and skipping of exon 2 which creates a premature stop codon in exon 3 (PMID: 12853981 (2003), 14508519 (2003)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.

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