Submissions for variant NM_000251.3(MSH2):c.1737A>G (p.Lys579=)

gnomAD frequency: 0.00138  dbSNP: rs61756467

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000030244	SCV000107281	likely benign	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Synonymous substitution with no effect on splicing, tested with an NMD inhibitor. Multifactorial likelihood analysis posterior probability 0.001-0.049
GeneDx	RCV000194267	SCV000170344	benign	not specified	2013-12-12	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000126818	SCV000212694	benign	Hereditary cancer-predisposing syndrome	2021-09-02	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.
Genetic Services Laboratory, University of Chicago	RCV000194267	SCV000248074	likely benign	not specified	2015-07-31	criteria provided, single submitter	clinical testing
Invitae	RCV001079889	SCV000252654	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528139	SCV000303160	benign	MSH2-related disorder	2020-01-10	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Color Diagnostics, LLC DBA Color Health	RCV000126818	SCV000537405	benign	Hereditary cancer-predisposing syndrome	2022-01-02	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000625240	SCV000744277	likely benign	Lynch syndrome 1	2017-06-28	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000625240	SCV000745642	likely benign	Lynch syndrome 1	2015-08-07	criteria provided, single submitter	clinical testing
Mendelics	RCV000625240	SCV001135742	likely benign	Lynch syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000679296	SCV001152280	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	MSH2: BP4, BP7
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000194267	SCV001156596	benign	not specified	2018-10-03	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000625240	SCV001299643	likely benign	Lynch syndrome 1	2019-05-07	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798019	SCV002042098	benign	Breast and/or ovarian cancer	2020-07-09	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000126818	SCV002534401	benign	Hereditary cancer-predisposing syndrome	2020-10-20	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000194267	SCV002552240	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000126818	SCV002819179	benign	Hereditary cancer-predisposing syndrome	2022-09-08	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000625240	SCV004015945	likely benign	Lynch syndrome 1	2023-07-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030244	SCV000052911	benign	Lynch syndrome	2015-02-17	no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000194267	SCV000257150	likely benign	not specified		no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353525	SCV000592518	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Lys579Lys variant has been identified in 5 out of 3696 proband chromosomes (frequency 0.001) in colorectal patients with Bethesda, Amsterdam or HNPCC criteria, and in 1 out of 400 control chromosomes (frequency 0.003) (Curia 1999, Scartozzi 2002, Auclair 2005, Mangold 2005, Pastrello 2011). it is listed in dbSNP database (‘with unknown allele’) (ID#: rs61756467) with an average heterozygosity of 0.002+/-0.030, therefore increasing the likelihood that this variant is benign. In addition, this variant is not expected to have clinical significance because it does not alter an amino acid residue, and is not located near a splice junction. In summary, based on the above information this variant is classified as Benign.
True Health Diagnostics	RCV000126818	SCV000805267	likely benign	Hereditary cancer-predisposing syndrome	2018-04-30	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000679296	SCV001922997	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000194267	SCV001931907	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000679296	SCV001959287	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000679296	SCV001977638	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000679296	SCV002036307	likely benign	not provided		no assertion criteria provided	clinical testing