Submissions for variant NM_000077.5(CDKN2A):c.343G>T (p.Val115Leu)

gnomAD frequency: 0.00002  dbSNP: rs779913365

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483515	SCV000566722	uncertain significance	not provided	2021-08-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with lung cancer (Tian 2020); This variant is associated with the following publications: (PMID: 28536309, 31721094, 27077911, 10432931, 22561520, 25149524)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000538411	SCV000637416	uncertain significance	Familial melanoma	2023-09-09	criteria provided, single submitter	clinical testing	The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts with different open reading frames. Both transcripts have been analyzed. We report either the variant with the higher classification or default to the CDKN2A (p16INK4a) variant. This report therefore includes the details for the CDKN2A (p16INK4a) variant. This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 115 of the CDKN2A (p16INK4a) protein (p.Val115Leu). This variant is present in population databases (no rsID available, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with CDKN2A (p16INK4a)-related conditions. This variant is also known as c.386G>T (p.Arg129Leu) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 419130). 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 tolerated. 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	RCV000776228	SCV000911434	uncertain significance	Hereditary cancer-predisposing syndrome	2025-02-10	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 valine with leucine at codon 115 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 childhood acute lymphoblastic leukemia (PMID: 34369425). This variant has been identified in 7/270730 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.
Ambry Genetics	RCV000776228	SCV001181775	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-06	criteria provided, single submitter	clinical testing	The p.V115L variant (also known as c.343G>T), located in coding exon 2 of the CDKN2A gene, results from a G to T substitution at nucleotide position 343. The valine at codon 115 is replaced by leucine, an amino acid with highly similar properties. This alteration has been reported in a Chinese lung cancer patient (Tian P et al. Pathol Oncol Res, 2020 Jan;26:109-114). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193449	SCV001362280	uncertain significance	not specified	2019-08-26	criteria provided, single submitter	clinical testing	Variant summary: CDKN2A c.343G>T (p.Val115Leu) results in a conservative amino acid change located in the Ankyrin repeat-containing domain (IPR020683) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.1e-05 in 239340 control chromosomes, predominantly at a frequency of 0.00028 within the East Asian subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, there are no reports of c.343G>T in individuals affected with Cutaneous Malignant Melanoma and no experimental evidence demonstrating an impact on protein function published in the literature. However, the variant has been predominantly reported as a somatic occurrence in multiple cancers (Ong_2012, Todorova_2015, Zhang_2016, Lih_2017). Three ClinVar submissions (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483515	SCV004221640	uncertain significance	not provided	2022-11-03	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00036 (7/19332 chromosomes in East Asian subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the c.343G>T (p.Val115Leu) variant has been reported as a somatic variant in individuals with Ewing Sarcoma (PMID: 27077911 (2016)) and laryngeal squamous cell carcinoma (PMID: 25149524 (2015)). Analysis of the c.343G>T (p.Val115Leu) variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of c.343G>T (p.Val115Leu) variant.
Baylor Genetics	RCV004568158	SCV005057263	uncertain significance	Melanoma and neural system tumor syndrome	2023-12-08	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005355929	SCV005920395	uncertain significance	Melanoma-pancreatic cancer syndrome	2023-11-21	criteria provided, single submitter	clinical testing