Submissions for variant NM_000077.5(CDKN2A):c.178G>A (p.Ala60Thr)

gnomAD frequency: 0.00001  dbSNP: rs769382085

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000463514	SCV000545520	uncertain significance	Familial melanoma	2024-05-15	criteria provided, single submitter	clinical testing	The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts with different open reading frames. Both transcripts have been analyzed. We report either the variant with the higher classification or default to the CDKN2A (p16INK4a) variant. This report therefore includes the details for the CDKN2A (p16INK4a) variant. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 60 of the CDKN2A (p16INK4a) protein (p.Ala60Thr). This variant is present in population databases (rs769382085, gnomAD 0.008%). This missense change has been observed in individual(s) with melanoma (PMID: 8023167). This variant is also known as c.221G>A (p.Gly74Asp) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 406705). 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: 21462282). 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.
Ambry Genetics	RCV001013163	SCV001173711	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-12	criteria provided, single submitter	clinical testing	The p.A60T variant (also known as c.178G>A), located in coding exon 2 of the CDKN2A gene, results from a G to A substitution at nucleotide position 178. The alanine at codon 60 is replaced by threonine, an amino acid with similar properties. In one study, this alteration was reported in 2 individuals without a history of melanoma, and not detected in any familial melanoma cases. Authors also performed a cell cycle arrest assay, which showed that this alteration causes a significant reduction in cell cycle arrest compared to wild-type (Miller PJ et al. Hum. Mutat. 2011 Aug;32(8):900-11). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001013163	SCV001350130	uncertain significance	Hereditary cancer-predisposing syndrome	2019-11-26	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 60 of the CDKN2A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Experimental functional studies have shown that this variant results in reduced cell cycle arrest activity (PMID 21462282). This variant has been reported in a melanoma tumor (PMID 8023167) and in the germline of two individuals without melanoma (PMID 21462282). This variant has been identified in 1/218966 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV002461188	SCV002756715	uncertain significance	not provided	2022-05-20	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge