Submissions for variant NM_002528.7(NTHL1):c.274C>T (p.Arg92Cys)

gnomAD frequency: 0.00086  dbSNP: rs148104494

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000592496	SCV000704487	uncertain significance	not provided	2016-12-08	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765258	SCV000896511	uncertain significance	Familial adenomatous polyposis 3	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000592496	SCV001042052	likely benign	not provided	2025-02-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001017807	SCV001178957	likely benign	Hereditary cancer-predisposing syndrome	2021-06-14	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.
GeneDx	RCV000592496	SCV001826661	uncertain significance	not provided	2024-09-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with ovarian cancer, breast cancer, adenomatous polyps, and leukemia (PMID: 30584090, 33332384, 33980861, 37834005); This variant is associated with the following publications: (PMID: 30584090, 29641532, 33980861, 33332384, 20054297, 32906206, 37834005)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000592496	SCV002047233	likely benign	not provided	2023-08-09	criteria provided, single submitter	clinical testing
Mendelics	RCV001800825	SCV002518403	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000765258	SCV002526088	uncertain significance	Familial adenomatous polyposis 3	2024-08-05	criteria provided, single submitter	clinical testing	The NTHL1 c.274C>T (p.Arg92Cys) missense change has a maximum subpopulation frequency of 0.13% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with colorectal cancer, breast cancer and precursor B-cell acute lymphoblastic leukemia (PMID: 32620917, 32295625, 32620917). It has also been identified in 3/1358 non-cancer controls collected as part of a study of individuals with multiple primary cancers (PMID: 29641532). To our knowledge, this variant has not been reported in individuals with NTHL1-associated polyposis. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Sema4, Sema4	RCV001017807	SCV002528953	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-30	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001800825	SCV002551608	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000765258	SCV002579693	uncertain significance	Familial adenomatous polyposis 3	2021-11-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000592496	SCV002585530	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	NTHL1: BP1
Clinical Genetics, Academic Medical Center	RCV000592496	SCV001919486	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000592496	SCV001953865	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000592496	SCV001974929	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003945401	SCV004769780	likely benign	NTHL1-related disorder	2023-05-04	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).