Submissions for variant NM_000077.5(CDKN2A):c.146T>G (p.Ile49Ser)

dbSNP: rs199907548

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493292	SCV000582968	likely pathogenic	not provided	2016-01-07	criteria provided, single submitter	clinical testing	The I49S variant has been published previously in association with melanoma (Holland et al., 1999; Begg et al., 2005; Goldstein et al., 2007; Lag et al, 2000). It 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. I49S is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position located within the ANK2 domain where amino acids with similar properties to isoleucine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (P48L, Q50R, V51F, M53V/T/I, M54I) have been reported in the Human Gene Mutation Database in association with melanoma (Stenson et al., 2014), supporting the functional importance of this region of the protein. Functional studies of the I49S variant have demonstrated that it results in reduced binding activity, altered localization, and increased proliferation in comparison to the wild type (Lal et al., 2000; McKenzie et al., 2010). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000528787	SCV000637392	likely pathogenic	Familial melanoma	2021-11-19	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 49 of the CDKN2A (p16INK4a) protein (p.Ile49Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with pancreatic adenocarcinoma and/or melanoma (PMID: 10398427, 10719365, 22841127, 28830827). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 430217). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 10719365, 20340136).
Genetics and Molecular Pathology, SA Pathology	RCV002272262	SCV002556812	pathogenic	Melanoma-pancreatic cancer syndrome	2020-09-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002395198	SCV002702201	pathogenic	Hereditary cancer-predisposing syndrome	2025-01-07	criteria provided, single submitter	clinical testing	The p.I49S pathogenic mutation (also known as c.146T>G), located in coding exon 1 of the CDKN2A gene, results from a T to G substitution at nucleotide position 146. The isoleucine at codon 49 is replaced by serine, an amino acid with dissimilar properties. This alteration has been identified in numerous familial melanoma cohorts, as well as in an individual with both melanoma and pancreatic cancer (Ambry internal data; Holland EA et al. Genes Chromosomes Cancer. 1999 Aug;25:339-48; Lal G et al. Genes Chromosomes Cancer. 2000 Apr;27:358-61; Begg CB et al. J. Natl. Cancer Inst. 2005 Oct;97:1507-15; Goldstein AM et al. J. Med. Genet. 2007 Feb;44:99-106; Miller PJ et al. Hum. Mutat. 2011 Aug;32:900-11; Maubec E et al. J. Am. Acad. Dermatol. 2012 Dec;67:1257-64). In addition, this alteration demonstrated defective CDK4 and CDK6 binding as well as increased rates of proliferation and abnormal subcelluar staining patterns (Lal G et al. Genes Chromosomes Cancer. 2000 Apr;27:358-61; McKenzie HA et al. Hum. Mutat. 2010 Jun;31:692-701). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Baylor Genetics	RCV003476189	SCV004212520	likely pathogenic	Melanoma and neural system tumor syndrome	2023-12-28	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002272262	SCV005084490	likely pathogenic	Melanoma-pancreatic cancer syndrome	2024-04-16	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 20340136, 10719365]. 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: 21462282, 10667595, 10398427, 22841127].
Color Diagnostics, LLC DBA Color Health	RCV002395198	SCV006063756	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-01-08	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 isoleucine with serine at codon 49 of the CDKN2A (p16INK4A) protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown that this variant causes a partial loss of protein function, as shown by subcellular mislocalization and decreased binding to CDK4 and CDK6 (PMID: 10719365, 20340136). This variant has been reported in five individuals affected with familial melanoma (PMID: 10398427, 12072543, 17218939, 22841127, 28830827) and in an individual affected with both melanoma and pancreatic cancer. (PMID: 10719365). In one family, this variant was observed in three siblings affected with melanoma (PMID: 10398427). This variant has also been reported in an individual with liposarcoma with a history of osteosarcoma in a first-degree relative (PMID: 28592523). 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 Likely Pathogenic.