Submissions for variant NM_000077.5(CDKN2A):c.266G>A (p.Gly89Asp)

dbSNP: rs137854599

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219725	SCV000275864	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-05-04	criteria provided, single submitter	clinical testing	The p.G89D variant (also known as c.266G>A), located in coding exon 2 of the CDKN2A gene, results from a G to A substitution at nucleotide position 266. The glycine at codon 89 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been reported as a highly penetrant Icelandic founder mutation in the CDKN2A gene with a significantly increased risk of melanoma, head and neck cancers, and pancreatic cancer in carrier families (Goldstein AM et al. J Med Genet. 2008 May;45(5):284-9). In an in vitro cell proliferation assay, this alteration was classified as functionally deleterious (Kimura H et al. Elife, 2022 01;11). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this 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.
GeneDx	RCV000493646	SCV000582103	pathogenic	not provided	2018-02-02	criteria provided, single submitter	clinical testing	The G89D variant in the CDKN2A gene has been reported as a highly penetrant risk allele which isstrongly associated with increased melanoma risk, and is theorized to be an Icelandic pathogenicfounder variant (Goldstein et al., 2008). The G89D variant was not observed in approximately 6,400individuals of European and African American ancestry in the NHLBI Exome Sequencing Project,indicating it is not a common benign variant in these populations. This substitution occurs at aposition that is not conserved. However, this position is within the ANK 3 repeat domain (Uniprot).The G89D variant is a non-conservative amino acid substitution, which is likely to impact secondaryprotein structure as these residues differ in polarity, charge, size and/or other properties, and in silicoanalysis predicts this variant is probably damaging to the protein structure/function. Multiple missensevariants in nearby residues have been reported in the Human Gene Mutation Database in associationwith CDKN2A-related disorders (Stenson et al., 2014), supporting the functional importance of thisregion of the protein. Based on the currently available evidence, we consider G89D to be pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000219725	SCV000906449	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-27	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 replaces glycine with aspartic acid at codon 89 of the CDKN2A (p16INK4A) protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant failed to suppress cell proliferation and showed cell cycle changes similar to known pathogenic variants (PMID: 35001868). This variant has been reported in multiple families and individuals affected with melanoma and/or pancreatic cancer (PMID: 18178632, 21462282, 33945383) and is reported to be associated with melanoma in a case-control study (PMID: 18178632). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Sema4, Sema4	RCV000219725	SCV002534324	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-09-12	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV003315501	SCV004018855	likely pathogenic	Melanoma-pancreatic cancer syndrome	2023-02-14	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 35001868]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 18178632, 33945383].
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000493646	SCV005196613	likely pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
OMIM	RCV000010033	SCV000030254	risk factor	Melanoma, cutaneous malignant, susceptibility to, 2	2017-08-17	no assertion criteria provided	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV000122946	SCV000166204	uncertain significance	Familial melanoma	2023-12-06	flagged submission	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 89 of the CDKN2A (p16INK4a) protein (p.Gly89Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with head and neck cancers, melanoma, and/or pancreatic carcinoma (PMID: 18178632; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9426). 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 have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 35001868). 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.