ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.197A>G (p.His66Arg) (rs756750256)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000564503 SCV000669168 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000564503 SCV000902850 likely benign Hereditary cancer-predisposing syndrome 2016-03-23 criteria provided, single submitter clinical testing
GeneDx RCV000236358 SCV000293520 likely benign not specified 2017-11-01 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000236358 SCV000919121 likely benign not specified 2018-05-01 criteria provided, single submitter clinical testing Variant summary: CDKN2A c.197A>G (p.His66Arg) 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 benign effect of the variant on protein function. The variant was found with an allele frequency of 8.6e-05 in 210102 control chromosomes (gnomAD), occurring exclusively within the East Asian cohort with a frequency (0.0011) that is approximately 4-folds higher than the estimated maximal expected allele frequency for a pathogenic variant (MPAF) in CDKN2A causing Cutaneous Malignant Melanoma phenotype (0.0003). However, in certain East Asian subpopulations the variant was observed with an even higher occurrence, e.g. in the Japanese control population it occurred with a frequency of 0.0117 (HGVD) that is approximately 40-folds higher than the estimated MPAF, strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.197A>G has been reported in the literature in several individuals with various tumor phenotypes, found as both germline and somatic occurrences (Ohnishi 1995, Morita 1998, Yonghao 1999, Hayano 2016, Fujita 1997, Ji 2015, Kim 2014, Takenaka 2015, Hwang 2017, Lee 2017), however these patients were exclusively of East Asian origin. These reports do not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cited variant as "likely benign" (2x) and "uncertain significance" (1x). Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV000461748 SCV000545523 likely benign Hereditary cutaneous melanoma 2018-01-04 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000564503 SCV000787993 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-20 no assertion criteria provided clinical testing

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