Submissions for variant NM_000077.5(CDKN2A):c.242C>G (p.Pro81Arg)

dbSNP: rs11552823

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000534720	SCV000637404	pathogenic	Familial melanoma	2021-06-24	criteria provided, single submitter	clinical testing	This sequence change replaces proline with arginine at codon 81 of the CDKN2A (p16INK4a) protein (p.Pro81Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with melanoma and multiple primary melanoma (PMID: 18023021, 21462282, 26800492, 19260062, 27804060). It has also been observed to segregate with disease in related individuals. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001015502	SCV001176342	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-07	criteria provided, single submitter	clinical testing	The p.P81R pathogenic mutation (also known as c.242C>G), located in coding exon 2 of the CDKN2A gene, results from a C to G substitution at nucleotide position 242. The proline at codon 81 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been detected in multiple cohorts of high-risk melanoma patients who either had multiple primary malignant melanomas and/or a family history of malignant melanoma as well as a pancreatic cancer patient (Helsing P et al. Genes Chromosomes Cancer, 2008 Feb;47:175-84; Müller C et al. Br. J. Dermatol., 2016 Jun;174:1308-17; Levin T et al. Fam. Cancer, 2017 Apr;16:257-265; Mantripragada KC et al. J Oncol Pract, 2016 Apr;12:e396-404). This alteration segregates with melanoma and pancreatic cancer in multiple individuals from multiple families (Levin T et al. Fam. Cancer, 2017 Apr;16:257-265; Ambry internal data). Based on internal structural analysis, this alteration lies within a mutational hotspot and will destabilize local structure of the binding interface leading to significantly impaired binding to CDK4 and CDK6 (Ambry internal data; Russo AA et al. Nature, 1998 Sep;395:237-43). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV001015502	SCV002052910	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-07	criteria provided, single submitter	clinical testing	This missense variant replaces proline with arginine at codon 81 of the CDKN2A (p16INK4A) protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. Other variants at this codon have been observed to be defective for CDK4 binding (PMID: 10389768, 20340136). This variant has been reported in individuals affected with melanoma and pancreatic cancer (PMID: 18023021, 26800492, 26907448, 27804060). This variant has not been identified 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	RCV004719859	SCV005325669	likely pathogenic	not provided	2023-08-03	criteria provided, single submitter	clinical testing	Identified in individuals with multiple primary melanomas, segregating with disease in relatives affected with melanoma or pancreatic cancer (Helsing et al., 2008; Levin et al., 2016; Muller et al., 2016); 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; This variant is associated with the following publications: (PMID: 21462282, 18023021, 9751050, 19260062, 26800492, 26907448, 27804060)