Submissions for variant NM_000251.3(MSH2):c.138C>G (p.His46Gln)

gnomAD frequency: 0.00019  dbSNP: rs33946261

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000664309	SCV000107166	likely benign	Lynch syndrome	2018-12-19	reviewed by expert panel	curation	Multifactorial likelihood analysis posterior probability <0.05
GeneDx	RCV001719811	SCV000149410	likely benign	not provided	2021-04-14	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 15872200, 27153395, 18383312, 24728327, 25637381, 23047549, 19389263, 15520370, 16741161, 18033691, 27601186, 28195393, 26333163, 26344056, 29212164, 28330790, 28125075, 28874130, 24055113, 25479140, 26951660, 29368341, 30374176, 31297992)
Invitae	RCV000076150	SCV000166262	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115501	SCV000172719	likely benign	Hereditary cancer-predisposing syndrome	2018-12-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Color Diagnostics, LLC DBA Color Health	RCV000115501	SCV000537523	likely benign	Hereditary cancer-predisposing syndrome	2022-01-03	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000121555	SCV000539682	uncertain significance	not specified	2016-03-28	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: 5 labs classify as VUS, including expert panel. No new information suggesting disease-causing role since expert classification.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121555	SCV000696213	likely benign	not specified	2023-07-10	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.138C>G (p.His46Gln) results in a non-conservative amino acid change located in the N-terminal domain (IPR007695) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00026 in 247506 control chromosomes, predominantly at a frequency of 0.00047 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (0.00026 vs 0.00057), allowing no conclusion about variant significance. c.138C>G has been identified in numerous patients with colorectal cancer (CRC), prostate cancer and ovarian cancer without strong evidence for causality (Examples: Barnetson_2008, Hampel_2005, Pal_2012, Grant_2015, Arora_2015, Lagerstedt-Robinson_2016, Maxwell_2016, Ghazani_2017, Raskin_2017, Rossi_2017, Velho_2018, Young_2018, Li_2020, Li_2021). In several studies, microsatellite stability in tumor tissues was assayed and found to be stable and immunohistochemical studies showed the presence of MSH2 (and MSH6) protein (Barnetson_2008, Hampel_2005, Arora_2015). In one patient, MLH1 was found to be hypermethylated at its promoter. This decreases the likelihood of this variant being a cause of germline inherited cancer as MLH1 promoter hypermethylation is associated with sporadic cancers instead of inherited cancers (Hampel_2005). In addition, one study reported the variant to not segregate with disease in a family, i.e. three affected individuals did not carry the variant, while three unaffected individuals carried the variant (Hansen_2017). Two independent in vitro functional studies demonstrated that the variant of interest does not impact mismatch repair activity (Houlleberghs_2016, Jia_2021). Another study that was performed on lymphoblastoid cells from a sporadic CRC patient who carried the variant, found increased level of DNA damage after UV treatment (Arora_2015). Since the patient's tumor sample showed stable microsatellites and normal expression of mismatch repair (MMR) proteins, the authors postulated that beyond its function in MMR, this variant might predispose to DNA double-strand breaks by affecting homologous recombinational repair. The following publications have been ascertained in the context of this evaluation (PMID: 18383312, 18033691, 15872200, 15520370, 23047549, 16574953, 25479140, 26951660, 27601186, 27153395, 28195393, 26344056, 28874130, 29212164, 28125075, 29945567, 29368341, 30374176, 31391288, 33471991, 33357406, 34117267). Multiple submitters including one expert panel (InSiGHT), have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as likely benign (n=12) and VUS (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000664309	SCV000788241	likely benign	Lynch syndrome	2018-04-26	criteria provided, single submitter	research	The MSH2 variant designated as NM_000251.2:c.138C>G (p.His46Gln) is classified as likely benign. This variant is listed in population databases and is found in approximately 1 out of 950 individuals of European ancestry, which is not consistent with the prevalence of Lynch syndrome. The variant has been seen in tumors with molecular phenotypes inconsistent with Lynch syndrome (InSiGHT.org). Based on in-silico scores the variant has a prior probability of pathogenicity of 10% or lower (Thompson et al., 2013, PMID:22949379). Cosegregation analysis of two observed families was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) yielded a combined likelihood ratio of 1.52:1 for this variant explaining cancer in the families (Thompson, et al., 2003, PMID:2900794). However, Bayesian analysis integrating all data (Tavtigian et al, 2018, PMID:29300386) gave a less than 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter MSH2 function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
Fulgent Genetics, Fulgent Genetics	RCV002477217	SCV000895477	likely benign	Lynch syndrome 1; Muir-Torré syndrome; Mismatch repair cancer syndrome 2	2022-04-25	criteria provided, single submitter	clinical testing
Mendelics	RCV000986643	SCV001135691	likely benign	Lynch syndrome 1	2023-02-27	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000986643	SCV001302263	uncertain significance	Lynch syndrome 1	2017-04-27	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798265	SCV002042089	uncertain significance	Breast and/or ovarian cancer	2020-12-09	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000121555	SCV002070914	likely benign	not specified	2021-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115501	SCV002528846	likely benign	Hereditary cancer-predisposing syndrome	2021-06-26	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121555	SCV002552183	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000986643	SCV002761451	likely benign	Lynch syndrome 1	2020-04-22	criteria provided, single submitter	clinical testing	The MSH2 c.138C>G variant is classified as Likely Benign (BS4, BP6, PP3) The MSH2 c.138C>G variant is a single nucleotide change in exon 1 of 16 of the MSH2 gene, which is predicted to change the amino acid histidine at position 46 in the protein to glutamine. This variant does not segregate with disease (BS4). PMID: 28195393- segregation analysis does not support pathogenicity. Variant identified in 0 out of 3 affected family members and 3 out of 9 unaffected family members. PMID:30374176 - family studies do not support pathogenicity
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001719811	SCV004220947	uncertain significance	not provided	2023-04-26	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with colorectal cancer and/or multiple adenomatous polyps (PMIDs: 15520370 (2004), 18033691 (2008), 28195393 (2017), 29212164 (2017)), ovarian cancer (PMID: 23047549 (2012)), breast cancer (PMIDs: 27153395 (2016), 29212164 (2017), 33471991 (2021), 35264596 (2022)), pancreatic cancer (PMID: 29945567 (2018)), and gliosarcomas (PMID: 33580181 (2021)). The variant has also been reported in unaffected individuals (PMIDs: 25637381 (2015), 33471991 (2021), 34117267 (2021)). Functional studies have conflicting reports as to whether the variant impacts MSH2 protein expression, stability, and repair (PMIDs: 1587220 (2005), 18033691 (2008), 26344056 (2015), 26344056 (2015), 26951660 (2016), 29212164 (2017), 33357406 (2021)). The frequency of this variant in the general population, 0.00073 (35/47650 chromosomes in North-Western European subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
PreventionGenetics, part of Exact Sciences	RCV003935012	SCV004749235	likely benign	MSH2-related condition	2023-08-14	criteria provided, single submitter	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).
ITMI	RCV000121555	SCV000085749	not provided	not specified	2013-09-19	no assertion provided	reference population
CSER _CC_NCGL, University of Washington	RCV000148631	SCV000190346	uncertain significance	Colorectal cancer	2014-06-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354246	SCV001548810	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH2 p.His46Gln variant was identified in 8 of 8869 proband chromosomes (frequency: 0.0009) from individuals or families with Lynch Syndrome, colorectal cancer, multiple adenomas, pancreatic cancer, or ovarian cancer and was identified in 1 of 3326 control chromosomes (frequency: 0.0003) from healthy individuals (Barnetson 2008, Fearnhead 2004, Grant 2015, Hampel 2005, Hansen 2017, Lagerstedt-Robinson 2016, Pal 2012, Rossi 2017). Segregation analysis of the variant in one family with colorectal cancer did not support pathogenicity as the variant was seen in both affected and unaffected family members (Hansen 2017). One study found the variant to be non-pathogenic using a site-specific mutagenesis screen (Houlleberghs 2016). The variant was identified in dbSNP (ID: rs33946261) as “With Likely benign, other allele”, ClinVar (classified as uncertain significance by an InSiGHT expert panel in 2015, Invitae, Color, and four other submitters; and as likely benign by GeneDx, Ambry Genetics, and one other submitter), UMD-LSDB (classified as UV), and Mismatch Repair Genes Variant Database. The variant was identified in control databases in 58 of 256068 chromosomes (1 homozygous) at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 55 (1 homozygous) of 115892 chromosomes (freq: 0.0005), African in 1 of 21856 chromosomes (freq: 0.00005), and Latino in 2 of 32620 chromosomes (freq: 0.00006); it was not observed in the “Other”, Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The p.His46 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.