ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.322G>A (p.Asp108Asn) (rs121913381)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000198618 SCV000254241 uncertain significance Hereditary melanoma 2020-08-15 criteria provided, single submitter clinical testing The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts that have different open reading frames. This sequence change replaces aspartic acid with asparagine at codon 108 of the CDKN2A (p16INK4a) protein (p.Asp108Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. Alternatively, this sequence change replaces arginine with glutamine at codon 122 of the CDKN2A (p14ARF) protein (p.Arg122Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several families affected with melanoma (PMID: 9416844, 16234564, 21462282). One of these families showed lack of consistent segregation with disease (PMID: 9416844). ClinVar contains an entry for this variant (Variation ID: 216275). This variant has been reported to have conflicting or insufficient data to determine the effect on CDKN2A (p16INK4a) protein function (PMID: 21462282, 12417717, 29091774). The functional impact of p.Arg122Gln on p14ARF has not been tested. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000482818 SCV000566201 uncertain significance not provided 2015-04-06 criteria provided, single submitter clinical testing This variant is denoted CDKN2A c.322G>A at the cDNA level, p.Asp108Asn (D108N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAT>AAT). This variant has been reported in several high-risk melanoma families (Flores 1997, Bishop 2002, Begg 2005, Goldstein 2006, Goldstein 2007, Aoude 2015). Additionally, Huot et al. (2002) identified CDKN2A Asp108Asn in an individual found to harbor a second CDKN2A variant (suspected biallelic). While an in vitro assay completed by Huot et al. (2002) showed that this variant results in a reduced ability to bind CDK4 and CDK6 compared to wild-type, another in vitro assay completed by Miller et al. (2011) showed the this variants retains cell cycle arrest function comparable to wild-type. CDKN2A Asp108Asn was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Aspartic Acid and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. CDKN2A Asp108Asn occurs at a position that is conserved across species and is not located in a known functional domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether CDKN2A Asp108Asn is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV001019323 SCV001180665 likely pathogenic Hereditary cancer-predisposing syndrome 2018-08-10 criteria provided, single submitter clinical testing The p.D108N variant (also known as c.322G>A), located in coding exon 2 of the CDKN2A gene, results from a G to A substitution at nucleotide position 322. The aspartic acid at codon 108 is replaced by asparagine, an amino acid with highly similar properties. This variant has been detected in multiple familial melanoma cohorts; however, in one family two of the four affected members did not carry the variant, and in another family one member also carried another pathogenic variant CDKN2A p.M53T (Flores JF et al. Oncogene. 1997 Dec;15:2999-3005; Aitken J et al. J. Natl. Cancer Inst. 1999 Mar;91:446-52; Bishop DT et al. J. Natl. Cancer Inst. 2002 Jun;94:894-903; Begg CB et al. J. Natl. Cancer Inst. 2005 Oct;97:1507-15; Goldstein AM et al. Cancer Res. 2006 Oct;66:9818-28; Berwick M et al. Cancer Epidemiol. Biomarkers Prev. 2006 Aug;15:1520-5; Orlow I et al. J. Invest. Dermatol. 2007 May;127:1234-43; Goldstein AM et al. J. Med. Genet. 2007 Feb;44:99-106; Huot TJ et al. Mol. Cell. Biol. 2002 Dec;22:8135-43; Miller PJ et al. Hum. Mutat. 2011 Aug;32:900-11). Two functional studies agree that this variant has an intermediate defect in binding to CDK4, however they disagree about whether there is a defect in CDK6 binding (Huot TJ et al. Mol. Cell. Biol. 2002 Dec;22:8135-43; Hallett ST et al. Cell Rep. 2017 Oct;21:1386-1398). One of these studies also reports that this variant causes a significant reduction in protein stability, however, this concept was not recapitulated in other functional studies with tagged-exogenous material (Hallett ST et al. Cell Rep. 2017 Oct;21:1386-1398; Huot TJ et al. Mol. Cell. Biol. 2002 Dec;22:8135-43, respectively). Lastly, another functional study showed that cell cycle arrest was not affected by this variant (Miller PJ et al. Hum. Mutat. 2011 Aug;32:900-11). CDKN2A p.D108N sits at the interface with other binding partners, including CDK4/6 and it is anticipated to result in a decrease in protein-protein interactions (Russo AA et al. Nature. 1998 Sep;395:237-43; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Health, Inc RCV001019323 SCV001349020 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-23 criteria provided, single submitter clinical testing
GenomeConnect, ClinGen RCV000482818 SCV001338890 not provided not provided no assertion provided phenotyping only Variant interpretted as Uncertain significance and reported on 06-22-2019 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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