ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.206A>G (p.Glu69Gly) (rs372670098)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166237 SCV000217017 likely pathogenic Hereditary cancer-predisposing syndrome 2018-02-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),Structural Evidence
Color RCV000166237 SCV000902849 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-23 criteria provided, single submitter clinical testing
GeneDx RCV000235616 SCV000292537 uncertain significance not provided 2018-03-12 criteria provided, single submitter clinical testing This variant is denoted CDKN2A c.206A>G at the cDNA level, p.Glu69Gly (E69G) at the protein level, and results in the change of a Glutamic Acid to a Glycine (GAG>GGG). This variant has been observed in at least two individuals with multiple primary melanomas and in at least two familial melanoma pedigrees, one of which also included pancreatic cancer; however, incomplete segregation with disease was observed (Goldstein 2006, Goldstein 2007, Kannengiesser 2009, Hatvani 2014). CDKN2A Glu69Gly was published in a melanoma case-control study, observed in 3/596 cases and absent among 476 unaffected controls (Harland 2014), but was also identified in at least one control individual in an acute lymphocytic leukemia case-control study (Xu 2015). CDKN2A Glu69Gly has also been observed in an individual with a Lynch syndrome-associated cancer and/or polyps who also carried a pathogenic MLH1 variant (Yurgelun 2015). Functional studies by McKenzie et al. (2010) demonstrated this variant led to minimal CDK4 and CDK6 binding, increased Ki67 index, and altered cellular localization of p16 protein compared to wild type, all suggestive of pathogenicity; however Kannengiesser et al. (2009) identified partial CDK4 binding ability. CDKN2A Glu69Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the second ANK2 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 Glu69Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000780107 SCV000917150 uncertain significance not specified 2018-09-25 criteria provided, single submitter clinical testing Variant summary: CDKN2A c.206A>G (p.Glu69Gly) results in a non-conservative amino acid change located in the Ankyrin repeat-containing domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-06 in 207602 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.206A>G has been reported in the literature in individuals affected with Cutaneous Malignant Melanoma. The variant has been found to lack cosegregation with disease being observed in unaffected individuals, along with being absent from affected individuals (Kannengiesser_2009, Miller_2011). These report(s) do not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma. Co-occurrences with other pathogenic variant(s) have been reported (MLH1 c.589-2A>G), providing supporting evidence for a benign role (Yurgelun_2015). Functional studies have found the variant to lead to effect CDK4 and CDK6 binding ability, Ki67 index and cellular locatization of p16 protein (McKenzie_2010, Kannengiesser_2009). Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant twice as uncertain significance and once as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000205699 SCV000262212 uncertain significance Hereditary cutaneous melanoma 2018-11-21 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 69 of the p16INK4a protein (p.Glu69Gly). The glutamic acid residue is weakly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is present in population databases (rs372670098, ExAC 0.002%). This variant has been reported in the literature in individuals affected with melanoma (PMID: 17047042, 24660985, 21325014). However, in the reported families this variant was absent from several affected individuals (PMID: 19260062), and in other families it was present in affected as well as unaffected individuals (PMID: 21462282). ClinVar contains an entry for this variant (Variation ID: 186615). Experimental studies have shown that this missense change impacts the functional ability of the p16INK4a protein to a degree that is intermediate between normal wild-type function and the impaired function of well-classified pathogenic variants (PMID: 19260062, 20340136). However, the clinical significance of this effect is unknown. 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.

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