Submissions for variant NM_000077.5(CDKN2A):c.122C>A (p.Pro41Gln)

gnomAD frequency: 0.00002  dbSNP: rs373407950

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129476	SCV000184246	benign	Hereditary cancer-predisposing syndrome	2023-01-27	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	RCV000465583	SCV000545552	uncertain significance	Familial melanoma	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 41 of the CDKN2A (p16INK4a) protein (p.Pro41Gln). This variant is present in population databases (rs373407950, gnomAD 0.05%). This missense change has been observed in individual(s) with pancreatic ductal adenocarcinoma and acute lymphoblastic leukemia (PMID: 26104880, 35171259). ClinVar contains an entry for this variant (Variation ID: 141111). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000129476	SCV000684506	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces proline with glutamine at codon 41 of the CDKN2A (p16INK4A) protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). An experimental functional study has reported this variant was neutral in a cell proliferation assay (PMID: 35001868). This variant has not been reported in individuals affected with CDKN2A-related disorders in the literature. This variant has been identified in 9/276116 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV000764830	SCV000895986	uncertain significance	Melanoma-pancreatic cancer syndrome; Melanoma, cutaneous malignant, susceptibility to, 2; Melanoma and neural system tumor syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781220	SCV000919120	uncertain significance	not specified	2017-10-20	criteria provided, single submitter	clinical testing	Variant summary: The CDKN2A c.122C>A (p.Pro41Gln) variant involves the alteration of a non-conserved nucleotide that lies within the ankyrin repeat-containing domain (InterPro). 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 9/271638 control chromosomes, observed exclusively in the East Asian subpopulation at a frequency of 0.000479 (9/18786). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic CDKN2A variant (0.0003), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. In addition, two clinical diagnostic laboratories have classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
GeneDx	RCV001588980	SCV001822900	uncertain significance	not provided	2023-01-23	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Published functional studies demonstrate neutral cell proliferation effects (Kimura et al., 2022); This variant is associated with the following publications: (PMID: 26104880, 35001868)
Baylor Genetics	RCV003474748	SCV004212500	uncertain significance	Melanoma and neural system tumor syndrome	2023-08-06	criteria provided, single submitter	clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153415	SCV003843797	likely pathogenic	Ovarian cancer	2022-01-01	flagged submission	clinical testing