Submissions for variant NM_000077.5(CDKN2A):c.197A>G (p.His66Arg)

gnomAD frequency: 0.00004  dbSNP: rs756750256

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001705313	SCV000293520	likely benign	not provided	2019-03-20	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 7478535, 7632931, 27338637, 27701467, 28489587, 21462282, 9823374, 25846456, 9133447, 7478613, 9037130, 12894891, 16354195, 28599463)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000461748	SCV000545523	likely benign	Familial melanoma	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000564503	SCV000669168	likely benign	Hereditary cancer-predisposing syndrome	2020-04-24	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	RCV000564503	SCV000902850	likely benign	Hereditary cancer-predisposing syndrome	2016-03-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000236358	SCV000919121	likely benign	not specified	2023-04-18	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 damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 216546 control chromosomes, predominantly at a frequency of 0.0011 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian 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 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 (example, Ohnishi_1995, Morita_1998, Yonghao_1999, Hayano_2016, Fujita_1997, Ji_2015, Kim_2014, Takenaka_2015, Hwang_2017, Lee_2017, Jiang_2018, Onidani_2019), 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. At least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA1 c.3770_3771delAG, p.Glu1257fs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3) and benign/likely benign (n=6). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics	RCV000988156	SCV001137773	uncertain significance	Melanoma-pancreatic cancer syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236358	SCV001470486	benign	not specified	2020-01-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000564503	SCV002534315	likely benign	Hereditary cancer-predisposing syndrome	2020-12-02	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000236358	SCV002760443	uncertain significance	not specified	2023-08-15	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
PreventionGenetics, part of Exact Sciences	RCV003907907	SCV004727047	likely benign	CDKN2A-related disorder	2020-07-17	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).