Submissions for variant NM_080911.3(UNG):c.262C>T (p.Arg88Cys)

gnomAD frequency: 0.00090  dbSNP: rs151095402

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000687269	SCV000605531	uncertain significance	Hyper-IgM syndrome type 5	2023-09-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000687269	SCV000814828	uncertain significance	Hyper-IgM syndrome type 5	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 88 of the UNG protein (p.Arg88Cys). This variant is present in population databases (rs151095402, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with colorectal cancer (PMID: 29546359). ClinVar contains an entry for this variant (Variation ID: 440391). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on UNG function (PMID: 22521144). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000506946	SCV001148812	uncertain significance	not provided	2016-06-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000687269	SCV001269368	likely benign	Hyper-IgM syndrome type 5	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000687269	SCV001984617	uncertain significance	Hyper-IgM syndrome type 5	2020-01-06	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000687269	SCV003828064	uncertain significance	Hyper-IgM syndrome type 5	2019-10-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000506946	SCV005202118	likely pathogenic	not provided	2024-09-24	criteria provided, single submitter	clinical testing	Published functional studies suggest that although R88C does not impact UNG protein expression, this variant disrupts interaction, binding, and colocalization with RPA2 (PMID: 22521144, 24910198); 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: 22521144, 24910198, 17029639, 36835215, 29546359, 23742752, 26935981, Conti2024[Preprint], 38746347, 39268404)
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000506946	SCV001741605	uncertain significance	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000506946	SCV001799666	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000506946	SCV001975852	uncertain significance	not provided		no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV000687269	SCV004228756	not provided	Hyper-IgM syndrome type 5		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 10-23-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.