Submissions for variant NM_000077.5(CDKN2A):c.198C>G (p.His66Gln)

dbSNP: rs374984975

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000695227	SCV000823713	uncertain significance	Familial melanoma	2024-12-23	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 histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 66 of the CDKN2A (p16INK4a) protein (p.His66Gln). This variant is present in population databases (rs374984975, gnomAD 0.001%). This variant has not been reported in the literature in individuals affected with CDKN2A (p16INK4a)-related conditions. This variant is also known as c.241C>G (p.Arg81Gly) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 573530). 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 tolerated. 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	RCV001013933	SCV001174577	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-29	criteria provided, single submitter	clinical testing	The p.H66Q variant (also known as c.198C>G), located in coding exon 2 of the CDKN2A gene, results from a C to G substitution at nucleotide position 198. The histidine at codon 66 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is not well 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	RCV001013933	SCV001355154	uncertain significance	Hereditary cancer-predisposing syndrome	2018-12-12	criteria provided, single submitter	clinical testing
GeneDx	RCV002473116	SCV002770253	uncertain significance	not provided	2024-03-28	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; This variant is associated with the following publications: (PMID: 16354195, 18538737, 30967399, 33134534)
Fulgent Genetics, Fulgent Genetics	RCV002507210	SCV002815177	uncertain significance	Melanoma-pancreatic cancer syndrome; Melanoma, cutaneous malignant, susceptibility to, 2; Melanoma and neural system tumor syndrome	2021-12-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509516	SCV002819837	uncertain significance	not specified	2022-12-27	criteria provided, single submitter	clinical testing	Variant summary: CDKN2A c.198C>G (p.His66Gln) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.7e-06 in 214172 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.198C>G has been reported in the literature in cancer cells from OPSCC and Melanoma patients, although the variant was not confirmed to be of a germline origin rather than somatic (Yang_2005, Khandelwal_2020). These reports do not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma. At least one publication reports experimental evidence evaluating an impact on p32 binding in the ARF protein, derived from an alternate transcript in which the variant would result in p.Arg81Gly (Itahana_2008). This showed that this residue occurs in or near a p32 binding domain and that the variant may inhibit p32 binding. Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 , and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.