ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.369T>A (p.His123Gln) (rs6413463)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254655 SCV000149245 likely benign not specified 2017-10-26 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.
Ambry Genetics RCV000115336 SCV000216974 benign Hereditary cancer-predisposing syndrome 2014-09-29 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Invitae RCV001080834 SCV000218934 benign Hereditary melanoma 2020-12-02 criteria provided, single submitter clinical testing
Counsyl RCV000411383 SCV000489539 uncertain significance Melanoma-pancreatic cancer syndrome 2016-10-19 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588888 SCV000601029 likely benign not provided 2019-08-09 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000254655 SCV000695344 likely benign not specified 2020-07-02 criteria provided, single submitter clinical testing Variant summary: CDKN2A c.369T>A (p.His123Gln) 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 damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00042 in 274982 control chromosomes, predominantly at a frequency of 0.0045 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 15 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDKN2A causing Cutaneous Malignant Melanoma phenotype (0.0003), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.369T>A has been reported in the literature in individuals affected with Noonan syndrome/glioneuronal tumors, rectal cancer, and one individual who met health insurance criteria for BRCA1/2 or Lynch syndrome gene testing without a specific phenotype being provided (Lin_2016, DeRycke_2017, Yorczyk_2015). These reports do not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma. In addition, at least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal cdk4 activity in-vitro (Byeon_1998). Co-occurrences with other pathogenic variants have been reported (BRCA1 c.2679_2682delGAAA, p.Lys893fsX106; PTPN11 c.923A>G, p.Asn308Ser), providing supporting evidence for a benign role. Eight ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (1x), likely benign (5x) and benign (2x). Based on the evidence outlined above, until more clinical and functional data become available, the variant was classified as likely benign.
PreventionGenetics,PreventionGenetics RCV000588888 SCV000805826 likely benign not provided 2017-03-20 criteria provided, single submitter clinical testing
Mendelics RCV000709065 SCV000838325 likely benign Cutaneous malignant melanoma 2 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115336 SCV000910615 benign Hereditary cancer-predisposing syndrome 2016-03-23 criteria provided, single submitter clinical testing
Mendelics RCV000411383 SCV001137760 likely benign Melanoma-pancreatic cancer syndrome 2019-05-28 criteria provided, single submitter clinical testing

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