Submissions for variant NM_002528.7(NTHL1):c.763C>T (p.Arg255Cys)

gnomAD frequency: 0.00005  dbSNP: rs779992803

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000814330	SCV000954734	uncertain significance	not provided	2024-01-31	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 263 of the NTHL1 protein (p.Arg263Cys). This variant is present in population databases (rs779992803, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with NTHL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 657672). 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. 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	RCV001026902	SCV001189374	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-14	criteria provided, single submitter	clinical testing	The p.R263C variant (also known as c.787C>T), located in coding exon 5 of the NTHL1 gene, results from a C to T substitution at nucleotide position 787. The arginine at codon 263 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000814330	SCV001777025	uncertain significance	not provided	2024-09-01	criteria provided, single submitter	clinical testing	Observed in an individual with breast cancer (PMID: 33980861); 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: 29641532, 33980861)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001789784	SCV002032290	uncertain significance	Familial adenomatous polyposis 3	2021-11-04	criteria provided, single submitter	clinical testing	The NTHL1 c.787C>T (p.Arg263Cys) missense change has a maximum subpopulation frequency of 0.012% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/16-2090162-G-A). Seven of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional assays. To our knowledge, this variant has not been reported in individuals with familial adenomatous polyposis. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PP3.
Sema4, Sema4	RCV001026902	SCV002529020	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-02	criteria provided, single submitter	curation
Baylor Genetics	RCV001789784	SCV004192080	uncertain significance	Familial adenomatous polyposis 3	2024-03-27	criteria provided, single submitter	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV001789784	SCV004228790	not provided	Familial adenomatous polyposis 3		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 12-07-2020 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.