Submissions for variant NM_000077.5(CDKN2A):c.194T>C (p.Leu65Pro)

dbSNP: rs1587332314

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001013721	SCV001174344	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-25	criteria provided, single submitter	clinical testing	The p.L65P pathogenic mutation (also known as c.194T>C), located in coding exon 2 of the CDKN2A gene, results from a T to C substitution at nucleotide position 194. The leucine at codon 65 is replaced by proline, an amino acid with similar properties. This alteration has been reported in individuals with a personal and/or family history of pancreatic cancer, atypical nevi and/or cutaneous malignant melanoma and has been shown to segregate with disease in one of these families (Ambry internal data; Landi MT et al. J. Med. Genet. 2004 Jul;41(7):557-66; Puig S et al. J. Clin. Oncol. 2005 May;23(13):3043-51; Goldstein AM et al. J. Med. Genet. 2007 Feb;44(2):99-106; Ghiorzo P et al. J. Med. Genet. 2012 Mar;49(3):164-70; Zhen DB et al. Genet. Med. 2015 Jul;17(7):569-77). Functional analysis of this variant is conflicting with one study showing a modest decrease in CDK4 binding while another study shows normal-to-intermediate rates of cell proliferation (Landi MT et al. J. Med. Genet. 2004 Jul;41(7):557-66; Scaini et al. Hum. Mutat. 2014 Jul;35(7):828-40). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Ambry internal data; Byeon IJ et al. Mol. Cell. 1998 Feb;1:421-31). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV001013721	SCV001357758	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-07-19	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with proline at codon 65 of the CDKN2A (p16INK4A) protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that the variant protein exhibits reduced binding to CDK4 in a yeast-based assay (PMID: 15235029) and some disruption in mammalian cell-based proliferation assays (PMID: 24659262, 35001868). This variant has been reported in multiple individuals affected with melanoma (PMID: 15235029, 16905682, 18024887, 21325014, 25780468, 26681309), pancreatic cancer (PMID: 22368299, 25356972), and osteosarcoma (PMID: 28592523). It has been shown that this variant segregates with melanomas in at least 4 individuals in a family (PMID: 15235029). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001873249	SCV002315979	likely pathogenic	Familial melanoma	2023-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 65 of the CDKN2A (p16INK4a) protein (p.Leu65Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a personal and/or family history of melanoma and pancreatic cancer (PMID: 15235029, 15860862, 18024887, 21325014, 22841127, 25780468, 26775776, 28592523, 36139606). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 820351). 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: 15235029, 35001868). 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.
Faculté Pluridciplinaire Nador, Université Mohamed Premier	RCV001250927	SCV001250918	likely pathogenic	Squamous cell lung carcinoma	2020-05-05	no assertion criteria provided	clinical testing