Submissions for variant NM_000077.5(CDKN2A):c.434T>C (p.Ile145Thr)

dbSNP: rs730881680

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160418	SCV000210951	uncertain significance	not provided	2023-06-08	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25980754)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000200632	SCV000254245	uncertain significance	Familial melanoma	2025-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 145 of the CDKN2A (p16INK4a) protein (p.Ile145Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CDKN2A (p16INK4a)-related conditions. ClinVar contains an entry for this variant (Variation ID: 182420). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The threonine 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	RCV000771213	SCV000903253	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-06	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 145 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). This variant has not been identified 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	RCV000771213	SCV001184060	likely benign	Hereditary cancer-predisposing syndrome	2020-05-13	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.
Sema4, Sema4	RCV000771213	SCV002534344	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-29	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003398823	SCV004122360	uncertain significance	not specified	2024-08-13	criteria provided, single submitter	clinical testing	Variant summary: CDKN2A c.434T>C (p.Ile145Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-06 in 1612484 control chromosomes (gnomAD database v4). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.434T>C has been reported in the literature in an individual that had multi gene panel testing performed for Lynch Syndrome (Yurgelun_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. The following publication have been ascertained in the context of this evaluation (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 182420). Based on the evidence outlined above, the variant was classified as uncertain significance.