Submissions for variant NM_080911.3(UNG):c.769T>C (p.Tyr257His)

gnomAD frequency: 0.00002  dbSNP: rs769188214

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000285151	SCV000375640	uncertain significance	Hyper-IgM syndrome type 5	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000520946	SCV000618779	uncertain significance	not provided	2017-07-07	criteria provided, single submitter	clinical testing	The Y257H variant in the UNG gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The Y257H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Y257H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret Y257H as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000285151	SCV003347401	uncertain significance	Hyper-IgM syndrome type 5	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 257 of the UNG protein (p.Tyr257His). This variant is present in population databases (rs769188214, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with UNG-related conditions. ClinVar contains an entry for this variant (Variation ID: 306978). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt UNG protein function with a negative predictive value of 80%. 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.
Ambry Genetics	RCV004021531	SCV004977950	uncertain significance	not specified	2023-11-09	criteria provided, single submitter	clinical testing	The c.769T>C (p.Y257H) alteration is located in exon 6 (coding exon 6) of the UNG gene. This alteration results from a T to C substitution at nucleotide position 769, causing the tyrosine (Y) at amino acid position 257 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.