Submissions for variant NM_000077.5(CDKN2A):c.320G>A (p.Arg107His)

gnomAD frequency: 0.00001  dbSNP: rs370823171

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160407	SCV000210940	uncertain significance	not provided	2024-09-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 16354195, 9823374, 26104880, 27294619, 21462282)
Ambry Genetics	RCV000221998	SCV000273497	likely benign	Hereditary cancer-predisposing syndrome	2018-12-20	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000464667	SCV000545549	uncertain significance	Familial melanoma	2023-11-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 107 of the CDKN2A (p16INK4a) protein (p.Arg107His). This variant is present in population databases (rs370823171, gnomAD 0.004%). This missense change has been observed in individual(s) with acute lymphoblastic leukemia (PMID: 26104880). ClinVar contains an entry for this variant (Variation ID: 182413). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV000221998	SCV000689602	uncertain significance	Hereditary cancer-predisposing syndrome	2025-01-13	criteria provided, single submitter	clinical testing	The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/). This missense variant replaces arginine with histidine at codon 107 of the CDKN2A (p16INK4A) protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with acute lymphoblastic leukemia (PMID: 26104880) and in an individual who was unaffected with melanoma (PMID: 21462282). This variant has been identified in 4/235684 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780105	SCV000917147	uncertain significance	not specified	2021-07-11	criteria provided, single submitter	clinical testing	Variant summary: CDKN2A c.320G>A (p.Arg107His) 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 benign effect of the variant on protein function. The variant allele was found at a frequency of 1.7e-05 in 235684 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.320G>A has been reported in the literature in one non melanoma carrier (Miller_2011) and in an individual with ALL (Xu_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=3, likely benign, n=1). At-least one submitter reports a non-specified co-occurrence with a pathogenic variant in another gene that clearly explained the patient phenotype. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV004567207	SCV005057225	uncertain significance	Melanoma and neural system tumor syndrome	2024-03-19	criteria provided, single submitter	clinical testing