ClinVar Miner

Submissions for variant NM_000077.5(CDKN2A):c.298G>T (p.Ala100Ser)

gnomAD frequency: 0.00038  dbSNP: rs200863613
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000588034 SCV000149242 uncertain significance not provided 2024-08-14 criteria provided, single submitter clinical testing Published functional studies are inconclusive: protein expression and protein binding comparable to wildtype, inconclusive cell cycle arrest activity, and reduced protein abundance and methylation (PMID: 9473234, 19141585, 21462282); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28866070, 9823374, 12461329, 9808520, 21462282, 19141585, 19360740, 9782052, 8841025, 26205736, 28767289, 11360201, 29533785, 16818274, 28765326, 18519632, 9751050, 27960642, 27756164, 12417040, 9473234, 9166859, 7718873, 35001868, 30038052)
Labcorp Genetics (formerly Invitae), Labcorp RCV000229571 SCV000283442 likely benign Familial melanoma 2024-01-22 criteria provided, single submitter clinical testing
Ambry Genetics RCV000570355 SCV000669175 likely benign Hereditary cancer-predisposing syndrome 2019-01-04 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health RCV000570355 SCV000689600 benign Hereditary cancer-predisposing syndrome 2021-01-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000855587 SCV000695338 benign not specified 2021-12-17 criteria provided, single submitter clinical testing Variant summary: CDKN2A c.298G>T (p.Ala100Ser) results in a 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 benign effect of the variant on protein function. The variant allele was found at a frequency of 9.7e-05 in 236362 control chromosomes, predominantly at a frequency of 0.0013 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 4-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.298G>T has been reported in the literature without strong evidence for causality (e.g. Yarbrough_1996, Gamieldien_1998, Klangby_1998, Yanagawa_2002, Agrawal_2009, Patel_2017, Shindo_2017, McWilliams_2018). These reports do not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma. Experimental evidence indicated that the variant does not significantly affect protein function (Lindstrom_2001, Miller_2011, Ng_2018). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant with as benign (n=2), likely benign (n=2) and VUS (n=2). Based on the evidence outlined above, the variant was classified as benign.
Mendelics RCV000988151 SCV001137764 likely benign Melanoma-pancreatic cancer syndrome 2024-04-09 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000855587 SCV001470488 benign not specified 2020-07-30 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000570355 SCV002534326 likely benign Hereditary cancer-predisposing syndrome 2021-05-10 criteria provided, single submitter curation

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