ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.194T>C (p.Leu65Pro) (rs1587332314)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001013721 SCV001174344 likely pathogenic Hereditary cancer-predisposing syndrome 2020-03-06 criteria provided, single submitter clinical testing The p.L65P variant (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 (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, this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Health, Inc RCV001013721 SCV001357758 likely pathogenic Hereditary cancer-predisposing syndrome 2020-11-03 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 inconclusive phenotype in a mammalian cell-based proliferation assay (PMID: 24659262). This variant has been reported in multiple individuals affected with melanomas (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.
Faculté Pluridciplinaire Nador,Université Mohamed Premier RCV001250927 SCV001250918 likely pathogenic Squamous cell lung carcinoma 2020-05-05 no assertion criteria provided clinical testing

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