Submissions for variant NM_000077.5(CDKN2A):c.149A>G (p.Gln50Arg)

dbSNP: rs587778189

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213788	SCV000276403	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-21	criteria provided, single submitter	clinical testing	The p.Q50R pathogenic mutation (also known as c.149A>G), located in coding exon 1 of the CDKN2A gene, results from an A to G substitution at nucleotide position 149. The glutamine at codon 50 is replaced by arginine, an amino acid with highly similar properties. This alteration has been detected in numerous melanoma and pancreatic cancer cohorts (Walker GJ et al. Hum. Mol. Genet. 1995 Oct;4:1845-52; Box NF et al. Am. J. Hum. Genet. 2001 Oct;69:765-73; Pollock PM et al. Genes Chromosomes Cancer. 2001 Sep;32:89-94; Zhen DB et al. Genet. Med. 2015 Jul;17:569-77; Bruno W et al. Oncotarget. 2018 Jun;9:28798; Ambry internal data). It was also found to segregate with melanoma in at least six melanoma-affected individuals in one family (Walker GJ et al. Hum. Mol. Genet. 1995 Oct;4:1845-52; Box NF et al. Am. J. Hum. Genet. 2001 Oct;69:765-73). Based on internal structural analysis, this amino acid substitution is anticipated to result in a significant decrease in structural stability (Russo AA et al. Nature. 1998 Sep;395:237-43; Ambry internal data). A different substitution at the same position (CDKN2A c.149A>C, p.Q50P) shows both a splice defect and defective CDK4 binding by the native protein harboring only the missense change (Loo JC et al. Oncogene. 2003 Sep; 22(41):6387-94). This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000471227	SCV000545524	likely pathogenic	Familial melanoma	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 50 of the CDKN2A (p16INK4a) protein (p.Gln50Arg). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with melanoma and/or pancreatic cancer (PMID: 8595405, 11477665, 11500805, 25356972, 26775776). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 232304). 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: 8573142, 35001868). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Color Diagnostics, LLC DBA Color Health	RCV000213788	SCV000689580	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-21	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with arginine at codon 50 in the ankyrin repeat 2 of the CDKN2A (p16INK4A) 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). Functional studies showed that this variant affected cell cycle control and failed to suppress cell proliferation (PMID: 35001868). Splice site prediction tools suggest that this variant may impact RNA splicing, although this prediction has not been investigated in RNA studies. This variant has been reported in individuals and families affected with melanoma (PMID: 11477665, 12072543, 16905682, 26681309, 26775776, 28830827, 29464027, 32455486; Cardelli 2020, dissertation, University of L'Aquila; Haghighat, et al. P-07, CGA-IGC 2022) and familial pancreatic cancer (PMID 25356972). This variant has been shown to segregate with disease in six related individuals affected with melanoma (PMID: 8595405). This variant has been identified in 1/249628 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Notably, a different nucleotide substitution at the same position, c.149A>C (p.Gln50Pro), has been observed in individuals affected with melanoma (Clinvar Variation ID: 187713) and shown to affect RNA splicing and p16INK4A protein function (PMID: 14508519). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000471227	SCV001339146	likely pathogenic	Familial melanoma	2020-03-31	criteria provided, single submitter	clinical testing	Variant summary: CDKN2A c.149A>G (p.Gln50Arg) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249628 control chromosomes. c.149A>G has been reported in the literature in individuals affected with melanoma (Walker_1995, Pollock_2001, Puig_2016, Bruno_2016) and familial pancreatic cancer (Zhen_2015). In one family, 6 transmissions of the variant allele and 1 transmission of the reference allele to affected individuals was reported (Walker_1995). These data indicate that the variant is likely to be associated with disease. Co-occurrence with a pathogenic variant has been reported (CHEK2 c.1283C>T, p.Ser428Phe), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV002222452	SCV002499795	likely pathogenic	not provided	2022-04-18	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: improper protein refolding and impaired ability to regulate cellular proliferation (Tang 1999, Kimura 2022); Observed in individuals with melanoma or pancreatic cancer and segregated with disease in at least one family (Walker 1995, Pollock 2001, Bishop 2002, Goldstein 2004, Goldstein 2007, Zhen 2015, Bruno 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21462282, 9461066, 18573309, 11500805, 23178718, 11477665, 15146471, 25356972, 12072543, 16905682, 10596908, 11687599, 9917418, 8595405, 9653180, 9529249, 16173922, 28830827, 26775776, 9751050, 9823374, 26619011, 26681309, 35001868)
Myriad Genetics, Inc.	RCV003316223	SCV004019325	likely pathogenic	Melanoma-pancreatic cancer syndrome	2023-02-09	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 35001868]. 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: 8595405, 11477665, 26775776, 25356972].
Baylor Genetics	RCV003475024	SCV004212533	likely pathogenic	Melanoma and neural system tumor syndrome	2022-06-03	criteria provided, single submitter	clinical testing
Database of Curated Mutations (DoCM)	RCV000431578	SCV000505917	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442170	SCV000505918	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424913	SCV000505919	likely pathogenic	Squamous cell carcinoma of the skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437789	SCV000505920	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442244	SCV000505921	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427856	SCV000505922	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438067	SCV000505923	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only