Submissions for variant NM_000251.3(MSH2):c.2154A>G (p.Gln718=)

gnomAD frequency: 0.00033  dbSNP: rs63750810

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076412	SCV000107441	likely benign	Lynch syndrome	2018-10-18	reviewed by expert panel	curation	Synonymous substitution with no effect on splicing tested with NMD inhibitor.
GeneDx	RCV000212616	SCV000170346	benign	not specified	2014-02-26	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	RCV000126820	SCV000212749	likely benign	Hereditary cancer-predisposing syndrome	2014-10-14	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.
Invitae	RCV001080051	SCV000252655	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000126820	SCV000685016	benign	Hereditary cancer-predisposing syndrome	2015-07-29	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679304	SCV000806026	likely benign	not provided	2017-03-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212616	SCV000917721	benign	not specified	2018-12-07	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.2154A>G alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00032 in 277216 control chromosomes, predominantly at a frequency of 0.00067 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.18 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Lynch Syndrome phenotype (0.00057), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.2154A>G has been reported in the literature in individuals affected with Lynch Syndrome (Mangold_2005, Renkonen_2003). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Additonally, one publication reports the variant to co-occur with a pathogenic variant, further evidence for the benign nature of this variant (Mangold_2005). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Mendelics	RCV000986682	SCV001135751	likely benign	Lynch syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000986682	SCV001300495	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.
CeGaT Center for Human Genetics Tuebingen	RCV000679304	SCV001502302	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	MSH2: BP4, BP7
Genetic Services Laboratory, University of Chicago	RCV000212616	SCV002071846	likely benign	not specified	2021-08-30	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000126820	SCV002534453	likely benign	Hereditary cancer-predisposing syndrome	2021-02-05	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212616	SCV002552256	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000986682	SCV004015963	likely benign	Lynch syndrome 1	2023-07-07	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000126820	SCV004228054	likely benign	Hereditary cancer-predisposing syndrome	2023-12-12	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492423	SCV004239280	likely benign	Breast and/or ovarian cancer	2022-10-12	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000679304	SCV001551622	likely benign	not provided		no assertion criteria provided	clinical testing	The MSH2 p.Gln718= variant was identified in 2 of 3494 proband chromosomes (frequency: 0.0006) from individuals or families with HNPCC (Mangold 2005, Renkonen 2003). The variant was also identified in dbSNP (ID: rs63750810) as "With other allele”, ClinVar (classified as benign by Invitae, GeneDx, and two other submitters; and as likely benign by InSiGHT expert panel, Prevention Genetics and Ambry Genetics), and UMD-LSDB (1x as neutral). The variant was identified in control databases in 90 of 277216 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6466 chromosomes (freq: 0.0002), Latino in 1 of 34420 chromosomes (freq: 0.00003), European in 85 of 126710 chromosomes (freq: 0.0007), Ashkenazi Jewish in 2 of 10152 chromosomes (freq: 0.0002), and East Asian in 1 of 18868 chromosomes (freq: 0.00005), while the variant was not observed in the African, Finnish, or South Asian populations. This variant was identified in a patient with an unspecified co-occurring, pathogenic variant (Mangold 2015). The p.Gln718= 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. However, 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predicts a greater than 10% 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000679304	SCV001808824	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000679304	SCV001926518	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000679304	SCV002037264	likely benign	not provided		no assertion criteria provided	clinical testing