Submissions for variant NM_000077.5(CDKN2A):c.405G>A (p.Gly135=)

gnomAD frequency: 0.00004  dbSNP: rs751586391

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001703784	SCV000523481	likely benign	not provided	2019-09-17	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 7478613, 1648379, 9132280, 7632931, 2877398, 7614482)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000474868	SCV000557469	benign	Familial melanoma	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000571462	SCV000669158	likely benign	Hereditary cancer-predisposing syndrome	2016-02-18	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	RCV000571462	SCV000684532	likely benign	Hereditary cancer-predisposing syndrome	2016-03-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000438522	SCV000919122	benign	not specified	2019-01-29	criteria provided, single submitter	clinical testing	Variant summary: CDKN2A c.405G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.1e-05 in 272432 control chromosomes, predominantly within the East Asian subpopulation at a frequency of 0.0011 in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 3.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDKN2A causing Cutaneous Malignant Melanoma phenotype (0.0003), suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. Moreover, the variant was also reported in Japanese healthy controls with a frequency of 0.0108 that is approximately 36-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/Japanese origin (HGVD). The variant, c.405G>A, has been reported in the literature in individuals from the Japanese population, who were affected with different types of cancer, however without evidence supporting causality (Igaki_1995, Ohnishi_1995, Morita_1998, Takahira_2004). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (1x) / likely benign (4x). Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000438522	SCV001470492	benign	not specified	2020-01-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000571462	SCV002534342	likely benign	Hereditary cancer-predisposing syndrome	2020-12-02	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000438522	SCV002760440	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000571462	SCV000787996	likely benign	Hereditary cancer-predisposing syndrome	2018-02-20	no assertion criteria provided	clinical testing