ClinVar Miner

Submissions for variant NM_000077.5(CDKN2A):c.197A>C (p.His66Pro)

dbSNP: rs756750256
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481730 SCV000567881 uncertain significance not provided 2016-07-13 criteria provided, single submitter clinical testing This variant is denoted CDKN2A c.197A>C at the cDNA level, p.His66Pro (H66P) at the protein level, and results in the change of a Histidine to a Proline (CAC>CCC). This variant has been observed in one family with history of melanoma and pancreatic cancer, but co-segregation studies were not completed (Lynch 2003). CDKN2A His66Pro was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Histidine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CDKN2A His66Pro occurs at a position that is not conserved and is located in the 2nd ANK repeat (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether CDKN2A His66Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000626782 SCV000747485 uncertain significance Melanoma 2017-01-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV002418502 SCV002722898 uncertain significance Hereditary cancer-predisposing syndrome 2022-01-26 criteria provided, single submitter clinical testing The p.H66P variant (also known as c.197A>C), located in coding exon 2 of the CDKN2A gene, results from an A to C substitution at nucleotide position 197. The histidine at codon 66 is replaced by proline, an amino acid with similar properties. This alteration was identified in a clinically suspicious hereditary breast/ovarian cancer family without a pathogenic variant in BRCA1 or BRCA2 (Bonache S et al. J Cancer Res Clin Oncol, 2018 Dec;144:2495-2513). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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