Submissions for variant NM_000077.5(CDKN2A):c.369T>A (p.His123Gln)

dbSNP: rs6413463

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000588888	SCV000149245	likely benign	not provided	2020-09-21	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27978560, 25318351, 22885699, 27626068, 18573309, 26601054, 16508961, 26366474, 26342236, 28944238, 26206375, 25186627, 9660926, 9823374, 7882348)
Ambry Genetics	RCV000115336	SCV000216974	benign	Hereditary cancer-predisposing syndrome	2014-09-29	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080834	SCV000218934	benign	Familial melanoma	2025-02-02	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	2022-11-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000254655	SCV000695344	benign	not specified	2021-09-04	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 0.0003 in 243602 control chromosomes, predominantly at a frequency of 0.0041 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 14 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 (example, Lin_2016, DeRycke_2017, Yorczyk_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma. Co-occurrences with other pathogenic variant(s) have been observed at our laboratory and in the literature (our laboratory, BRCA1 c.2679_2682delGAAA, p.Lys893fsX106; Lin_2016, PTPN11 c.923A>G, p.Asn308Ser), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant as evidenced by similar cell proliferation and viability levels as wild-type CDKN2A (Kwong-Shing Ng_2018). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a majority consensus leaning towards a likely benign/benign outcome. Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV000588888	SCV000805826	likely benign	not provided	2017-03-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	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
Sema4, Sema4	RCV000115336	SCV002534333	benign	Hereditary cancer-predisposing syndrome	2021-01-08	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000411383	SCV004018564	likely benign	Melanoma-pancreatic cancer syndrome	2023-09-14	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000254655	SCV004027436	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000588888	SCV004562065	likely benign	not provided	2023-08-17	criteria provided, single submitter	clinical testing