ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.373G>C (p.Asp125His) (rs146179135)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122948 SCV000166206 uncertain significance Hereditary melanoma 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 125 of the CDKN2A (p16INK4a) protein (p.Asp125His). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is present in population databases (rs146179135, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with pancreatic cancer (PMID: 26483394), individuals and families affected with melanoma (PMID: 10398427, 12072543, 17218939, 19320745, 25780468), and unaffected individuals (PMID: 22703879, 25780468, 18335566). ClinVar contains an entry for this variant (Variation ID: 41577). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000166832 SCV000217646 likely benign Hereditary cancer-predisposing syndrome 2019-11-12 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Other strong data supporting benign classification
GeneDx RCV000034479 SCV000292540 uncertain significance not provided 2018-07-12 criteria provided, single submitter clinical testing This variant is denoted CDKN2A c.373G>C at the cDNA level, p.Asp125His (D125H) at the protein level, and results in the change of an Aspartic Acid to a Histidine (GAT>CAT). This variant has been observed in multiple individuals with melanoma and in at least two childhood cases of acute lymphoblastic leukemia (Holland 1999, Bishop 2002, Goldstein 2004, Begg 2005, Orlow 2007, Capanu 2008, Council 2009, Xu 2015). In addition, CDKN2A Asp125His was shown to segregate with melanoma in two members of one family (Holland 1999), but was reported to not segregate with disease in other families (Cust 2011). CDKN2A Asp125His was observed at an allele frequency of 0.021% (26/123,350) in individuals of Non-Finnish European ancestry in large population cohorts and in 1/565 individuals with atherosclerosis, with no specific information about cancer history (Johnston 2012, Lek 2016). This variant is located in ANK 4 repeat (UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether CDKN2A Asp125His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000410592 SCV000488760 uncertain significance Melanoma-pancreatic cancer syndrome 2016-08-24 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000855586 SCV000695345 uncertain significance not specified 2019-09-06 criteria provided, single submitter clinical testing Variant summary: CDKN2A c.373G>C (p.Asp125His) results in a non-conservative amino acid change located in the Ankyrin repeat-containing domain (IPR020683) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 243848 control chromosomes, predominantly within the Non-Finnish Europeans, at a frequency of 0.00018, in the gnomAD database (exomes dataset). The variant was found with even higher allele frequency in the North-western European subpopulation (0.0004), and this frequency is higher than the expected maximum for a pathogenic variant in CDKN2A causing Cutaneous Malignant Melanoma (0.0003), suggesting that the variant might be a benign polymorphism. The variant, c.373G>C, has been reported in the literature in multiple individuals affected with Cutaneous Malignant Melanoma, and with other tumor phenotypes, including acute lymphoblastic leukemia, colorectal-, pancreatic- and breast cancer. These reports do not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma, or other types of cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as VUS (6x) and likely benign (1x). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics,PreventionGenetics RCV000034479 SCV000805827 uncertain significance not provided 2017-08-18 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034479 SCV000888055 uncertain significance not provided 2018-04-17 criteria provided, single submitter clinical testing
Color Health, Inc RCV000166832 SCV000902694 likely benign Hereditary cancer-predisposing syndrome 2016-08-08 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034479 SCV000043252 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.

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