Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000493314 | SCV000581510 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-07-12 | criteria provided, single submitter | clinical testing | The p.H83Q pathogenic mutation (also known as c.249C>A), located in coding exon 2 of the CDKN2A gene, results from a C to A substitution at nucleotide position 249. The histidine at codon 83 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in multiple individuals with melanoma as well as an Italian familial melanoma kindred (Begg CB et al. J Natl Cancer Inst. 2005 Oct 19;97(20):1507-15; Berwick M et al. Cancer Epidemiol Biomarkers Prev. 2006 Aug;15(8):1520-5; Orlow I et al. J Invest Dermatol. 2007 May;127(5):1234-43; Pedace L et al. Cancer Epidemiol. 2011 Dec;35(6):e116-20). Additionally, two disease-causing mutations, p.H83Y and p.H83N, have been described in the same codon (Yarbrough WG et al. J Natl Cancer Inst. 1999 Sep 15;91(18):1569-74; Lang J et al. Br J Dermatol. 2005 Dec;153(6):1121-5). This alteration has been observed in individuals who have a personal or family history that is consistent with CDKN2A-associated disease (Ambry internal data). Based on internal structural assessment, this alteration disrupts the ankyrin domain near its interface with kinases (Ambry internal data; Russo AA et al. Nature.1998 Sep;395(6699):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. |
| Labcorp Genetics |
RCV000693300 | SCV000821162 | uncertain significance | Familial melanoma | 2023-12-29 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 83 of the CDKN2A (p16INK4a) protein (p.His83Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with sporadic or familial melanoma (PMID: 16234564, 16307646, 16896043, 17218939, 20876876, 21462282, 21507037, 21893440, 28146043, 32221274). This variant is also known as c.247C>A, c.295C>A. ClinVar contains an entry for this variant (Variation ID: 429110). 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. 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001328378 | SCV001519499 | uncertain significance | not specified | 2021-03-07 | criteria provided, single submitter | clinical testing | Variant summary: CDKN2A c.249C>A (p.His83Gln) results in a non-conservative amino acid change located in the Ankyrin repeat containing domain (IPR020683) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 231524 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.249C>A has been reported in the literature in at-least one patient with Single primary melanoma with authorship/patient overlap among subsequent studies (example, Begg_2005, Berwick_2006, Orlow_2007), in at-least one patient in the melanoma genetics consortium cohort (Demenais_2010), a patient with sporadic melanoma with no reported family history (Miller_2011), in the setting of familial melanoma originating from Italy with no reported co-segregation evidence and possible cohort overlap (example, Pedace_2011, Pellegrini_2017, De Simone_2020). These report(s) do not provide unequivocal conclusions about association of the variant with inherited Cutaneous Malignant Melanoma. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic and one laboratory classified the variant as uncertain significance citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance. |