Submissions for variant NM_000251.3(MSH2):c.2400A>G (p.Leu800=)

gnomAD frequency: 0.00006  dbSNP: rs201298777

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212619	SCV000211253	benign	not specified	2014-08-25	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	RCV000160651	SCV000212862	likely benign	Hereditary cancer-predisposing syndrome	2014-06-03	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.
Eurofins Ntd Llc (ga)	RCV000724817	SCV000226006	uncertain significance	not provided	2015-05-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083867	SCV000253155	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000410686	SCV000430935	uncertain significance	Lynch syndrome 1	2018-01-12	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Counsyl	RCV000410686	SCV000489650	likely benign	Lynch syndrome 1	2016-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160651	SCV000690070	likely benign	Hereditary cancer-predisposing syndrome	2015-07-27	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000410686	SCV000744281	likely benign	Lynch syndrome 1	2017-06-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212619	SCV000919695	likely benign	not specified	2019-08-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000724817	SCV002047039	likely benign	not provided	2022-09-02	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000160651	SCV002534472	likely benign	Hereditary cancer-predisposing syndrome	2021-03-10	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000724817	SCV002822646	likely benign	not provided	2022-11-01	criteria provided, single submitter	clinical testing	MSH2: BP4, BP7
Myriad Genetics, Inc.	RCV000410686	SCV004018384	benign	Lynch syndrome 1	2023-03-22	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354589	SCV001549238	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH2 p.Leu800= variant was not identified in the literature. The variant was identified in dbSNP (ID: rs201298777) as "With other allele ", ClinVar (classified as benign by GeneDx; as likely benign by Ambry Genetics, Invitae, Counsyl, and Color; and as uncertain significance by three submitters), and in UMD-LSDB (1x as neutral). The variant was identified in control databases in 14 of 277180 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 14 of 126676 chromosomes (freq: 0.0001), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Leu800= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer,) do not predict a difference in splicing. In summary, based on the above information, 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 likely benign.
Clinical Genetics, Academic Medical Center	RCV000724817	SCV001920688	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537295	SCV004744081	likely benign	MSH2-related disorder	2019-05-14	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).