ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.318G>A (p.Val106=) (rs199888003)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000160416 SCV000214026 uncertain significance Hereditary cancer-predisposing syndrome 2014-06-10 criteria provided, single submitter clinical testing
Color RCV000160416 SCV000902687 likely benign Hereditary cancer-predisposing syndrome 2016-05-19 criteria provided, single submitter clinical testing
GeneDx RCV000590444 SCV000210949 uncertain significance not provided 2018-12-18 criteria provided, single submitter clinical testing This variant is denoted CDKN2A c.361G>A at the cDNA level, p.Ala121Thr (A121T) at the protein level, and results in the change of an Alanine to a Threonine (GCG>ACG) in exon 2 of the p14-ARF protein. Of note, the CDKN2A gene encodes the p16 protein, and using an alternate reading frame, the p14-ARF protein as well. This variant also results in a change to the p16 protein; however, that nucleotide substitution is silent (p.Val106Val) at the protein level. This variant, also reported as CDKN2A Ala162Thr, was observed in several individuals with melanoma or pancreatic cancer, several individuals with childhood leukemia, and an individual with a personal history of a Lynch syndrome-related cancer and/or polyps (Begg 2005, Erlandson 2007, Orlow 2007, McWilliams 2011, Aoude 2015, Burgstaller-Muehlbacher 2015, Grant 2015, Puig 2015, Xu 2015, Yurgelun 2015, Chaffee 2018). CDKN2A Ala121Thr was observed at an allele frequency of 0.05% (60/120,190) in individuals of European (non-Finnish) ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether CDKN2A Ala121Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000590444 SCV000695342 uncertain significance not provided 2016-07-01 criteria provided, single submitter clinical testing Variant summary: The CDKN2A c.318G>A (p.Val106Val) variant involves the alteration of a non-conserved nucleotide located in the coding region of both p16INK4A and p14ARF. It results in an alanine-to-threonine change in p14ARF (p.A121T) and a synonymous change in p16INK4A. In p14ARF the variant is predicted to add a possible glycosylation and phosphorylation site and also introduces a phosphoprotein-binding FHA domain implicated in DNA damage response and cell cycling (Xu_2015). One in silico tool predicts a damaging outcome for this variant along with 5/5 slice site tools predicting no significant impact on normal splicing. This variant was found in 12/112972 control chromosomes at a frequency of 0.0001062, which does not exceed the estimated maximal expected allele frequency of a pathogenic CDKN2A variant (0.0003). It was reported in several melanoma, bladder cancer, pancreatic cancer and childhood leukemia patients, however without strong evidence for pathogenicity and in one family, the variant showed lack of co-segregation with melanoma. One study showed that this variant was over-represented in acute lymphoblastic leukaemia compared to controls (Xu_2015). Multiple clinical diagnostic laboratories classified this variant as VUS or Likely Benign. Based on the available information, the pathogenicity or neutrality of the variant cannot be established with certainty; therefore, it was classified as variant of uncertain significance until more information becomes available.
Invitae RCV000122947 SCV000166205 likely benign Hereditary cutaneous melanoma 2017-01-10 criteria provided, single submitter clinical testing
PreventionGenetics RCV000590444 SCV000805824 likely benign not provided 2017-09-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212401 SCV000601025 uncertain significance not specified 2016-10-27 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590444 SCV000888053 likely benign not provided 2018-07-12 criteria provided, single submitter clinical testing

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