Submissions for variant NM_000251.3(MSH2):c.23C>T (p.Thr8Met)

gnomAD frequency: 0.00184  dbSNP: rs17217716

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076466	SCV000107495	no known pathogenicity	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability <0.001
Invitae	RCV001082308	SCV000166272	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000434381	SCV000170341	benign	not provided	2018-11-15	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30333958, 21681552, 22290698, 25371881, 23760103, 24728327, 10777691, 26332594, 21615986, 15340835, 15849733, 16810763, 18383312, 26951660, 28580595, 30998989, 31237724)
Ambry Genetics	RCV000130682	SCV000185569	benign	Hereditary cancer-predisposing syndrome	2014-09-03	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Illumina Laboratory Services, Illumina	RCV000144624	SCV000430908	likely benign	Lynch syndrome 1	2018-03-06	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000434381	SCV000511017	benign	not provided	2017-02-09	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130682	SCV000685038	benign	Hereditary cancer-predisposing syndrome	2015-03-05	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000144624	SCV000781766	uncertain significance	Lynch syndrome 1	2016-11-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000121556	SCV000806029	benign	not specified	2017-06-15	criteria provided, single submitter	clinical testing
Mendelics	RCV000144624	SCV001135688	benign	Lynch syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000121556	SCV001156593	benign	not specified	2018-09-21	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130682	SCV002534471	benign	Hereditary cancer-predisposing syndrome	2020-10-09	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000434381	SCV002544031	benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	MSH2: BS1, BS2
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121556	SCV002552182	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002498369	SCV002807667	likely benign	Lynch syndrome 1; Muir-Torré syndrome; Mismatch repair cancer syndrome 2	2022-05-21	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149750	SCV003838293	benign	Breast and/or ovarian cancer	2021-12-13	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000130682	SCV004228015	benign	Hereditary cancer-predisposing syndrome	2023-08-01	criteria provided, single submitter	clinical testing
ITMI	RCV000121556	SCV000085750	not provided	not specified	2013-09-19	no assertion provided	reference population
Pathway Genomics	RCV000144624	SCV000189951	likely benign	Lynch syndrome 1	2014-07-24	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353559	SCV000592449	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Thr8Met variant has been identified in 7/4128 proband chromsomes in individuals with Lynch syndrome, and was also identified in 2/200 control chromosomes (Ali 2012, Chao 2008, Mangold 2005, Nomura 2000, Valentin 2011, Wang 2006, Wei 2011), increasing the likelihood that this is a benign variant. The variant has also been reported in the HGMD, LOVD and several colon cancer databases, some of which suggest that it is probably neutral. It is listed in the dbSNP database as coming from a "clinical source" (ID#: rs17217716) with a MAF score of 0.008 (1000 Genomes) and it is observed at low frequency in the Han Chinese and Japanese HapMap population samples, increasing the likelihood this variant may be a common low frequency variant with no clinical significance. The p.Thr8 residue is conserved across mammals but computational analyses (SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of this variant cannot be determined with certainty at this time, although we would lean towards a more benign role for this variant. This variant is classified as Predicted Benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000121556	SCV000691894	likely benign	not specified		no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000130682	SCV000788032	likely benign	Hereditary cancer-predisposing syndrome	2018-03-02	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000121556	SCV001809338	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000121556	SCV001953189	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000121556	SCV001970363	benign	not specified		no assertion criteria provided	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000121556	SCV003839735	benign	not specified	2022-11-17	no assertion criteria provided	clinical testing