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 2020-04-02 criteria provided, single submitter clinical testing The p.E69G variant (also known as c.206A>G), located in coding exon 2 of the CDKN2A gene, results from an A to G substitution at nucleotide position 206 of the p16 protein-encoding isoform. The glutamic acid at codon 69 is replaced by glycine, an amino acid with similar properties. This alteration does not result in an amino-acid change in the p14-encoding isoform of CDKN2A. This variant was detected in numerous familial melanoma or multiple primary melanoma patients from Europe, North America and Australia; however, it did not segregate completely with disease (Goldstein AM et al. Cancer Res. 2006 Oct; 66(20):9818-28; Harland M et al. Hered Cancer Clin Pract 2014;12(1):20; Kannengiesser C et al. Hum. Mutat. 2009 Apr; 30(4):564-74; Hatvani Z et al. Exp. Dermatol. 2014 May;23(5):361-4; Cust AE et al. J. Med. Genet., 2011 Apr;48:266-72; Miller PJ et al. Hum. Mutat., 2011 Aug;32:900-11; Chaudru V et al. Fam. Cancer, 2009 May;8:371-7). This variant showed increased growth as well as decreased binding to both CDK6 and CDK4, although the CDK4 binding defect may be intermediate with respect to other known pathogenic CDKN2A missense mutations (Kannengiesser C et al. Hum. Mutat. 2009 Apr; 30(4):564-74; McKenzie HA et al. Hum. Mutat. 2010 Jun; 31(6):692-701). Based on internal structural analysis, this amino acid lies within the probable CDK4 binding site and is in close contact with other amino acids at which other pathogenic missense substitutions are found; however the change from glutamic acid to glycine is predicted to only mildly destabilize local structure and protein-protein binding interactions (Ambry internal data; Kannengiesser C et al. Hum. Mutat. 2009 Apr; 30(4):564-74; Russo AA et al. Nature, 1998 Sep;395:237-43). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000205699 SCV000262212 uncertain significance Hereditary melanoma 2020-10-15 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 observed in individual(s) 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.
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.
Color Health, Inc RCV000166237 SCV000902849 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-15 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with glycine at codon 69 of the CDKN2A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown conflicting results, with one study showing ~30% reduction in CDK4 binding (PMID: 19260062) and another study showing complete loss of CDK4/CDK6 binding (PMID: 20340136). This variant has been reported in individuals affected with melanoma (PMID: 17047042, 19260062, 19484507, 21325014, 21462282, 24660985, 25780468) and colorectal cancer (PMID: 25980754, 28135145). However, the variant was present in unaffected individuals (PMID: 21462282, 26104880) and absent in melanoma-affected individuals (PMID: 19260062) within the same family. This variant has been observed together with pathogenic BRCA2 mutations in two unrelated families and with a CHEK2 mutation in a family with a history of melanoma and prostate cancer (Color internal data). This variant has been identified in 2/211552 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780107 SCV000917150 uncertain significance not specified 2019-09-12 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 9.5e-06 in 211552 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The varianr, c.206A>G, has been reported in the literature in individuals affected with Cutaneous Malignant Melanoma (Chandru_2009, Cust_2011, Goldstein_2006, Hatvani_2014, Miller_2011). The variant has been found to lack co-segregation with disease being observed in unaffected individuals, along with being absent from affected individuals (Kannengiesser_2009, Miller_2011). These reports do not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma. Co-occurrence with another pathogenic variant has been reported (MLH1 c.589-2A>G) (Yurgelun_2015), providing supporting evidence for a benign role. Functional studies report the variant leads to effect CDK4 and CDK6 binding ability, Ki67 index and cellular locatization of p16 protein (McKenzie_2010, Kannengiesser_2009). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (3x VUS, 1x likely pathogenic). Based on the evidence outlined above, the variant was classified as uncertain significance.

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