Submissions for variant NM_000251.3(MSH2):c.2732T>G (p.Leu911Arg)

gnomAD frequency: 0.00007  dbSNP: rs41295182

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000524397	SCV000166278	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129717	SCV000184520	likely benign	Hereditary cancer-predisposing syndrome	2019-04-10	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.
GeneDx	RCV000589745	SCV000211223	uncertain significance	not provided	2020-01-29	criteria provided, single submitter	clinical testing	Published functional studies demonstrate no damaging effect: variant did not result in 6TG-resistant colony formation, suggesting it does not affect mismatch repair function (Houlleberghs 2016); Observed in individuals with colon or epithelial ovarian cancer (Loader 2002, Barnetson 2008, Pal 2012, Ghazani 2017, Raskin 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29684080, 22949387, 16379545, 18033691, 23047549, 12537652, 26092435, 26333163, 19389263, 21153778, 28125075, 26951660, 29212164, 29641532, 32634176)
Pathway Genomics	RCV000172810	SCV000223776	uncertain significance	Lynch syndrome 1	2014-10-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129717	SCV000292152	likely benign	Hereditary cancer-predisposing syndrome	2016-07-29	criteria provided, single submitter	clinical testing
Counsyl	RCV000172810	SCV000488405	uncertain significance	Lynch syndrome 1	2016-03-17	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000235177	SCV000539686	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: Multiple reports describe as VUS/benign, ExAC: 0.02% (12/64562) European chromosomes
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000235177	SCV000696255	likely benign	not specified	2023-08-14	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.2732T>G (p.Leu911Arg) results in a non-conservative amino acid change located in the Helix-turn-helix domain (aa 856-934) (Houlleberghs_2016) 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 6.8e-05 in 251846 control chromosomes, predominantly at a frequency of 0.00014 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (6.8e-05 vs 0.00057), allowing no conclusion about variant significance. c.2732T>G has been reported in the literature in individuals affected with colon cancer (e.g. Loader_2002, Barnetson_2008, Ghazani_2017, Raskin_2017), in a patient with ovarian cancer (Pal_2012), and in a patient with endometrial and breast cancer (Singh_2020). The variant was also found in unaffected individuals (Karageorgos_2015, Arora_2015). One of these studies reported the variant not to segregate with the disease in a family (Barnetson_2008). At least one publication reported experimental evidence evaluating an impact on protein function, and showed no damaging effect for this variant on MMR activity in mouse embryonic stem cells (Houlleberghs_2016). An additional sstudy reported the vairant to be neutral using a combination of deep mutational scanning with established MMR assay (Jia_2021). The following publications have been ascertained in the context of this evaluation (PMID: 18033691, 23047549, 26092435, 26951660, 26344056, 29212164, 28125075, 12537652, 32634176, 33357406). 13 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments ranging from VUS to likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV004528276	SCV000806035	uncertain significance	MSH2-related disorder	2023-07-26	criteria provided, single submitter	clinical testing	The MSH2 c.2732T>G variant is predicted to result in the amino acid substitution p.Leu911Arg. This variant has been previously reported in individuals with colorectal cancer (Barnetson et al. 2008. PubMed ID: 18033691; Table S1, Raskin et al. 2017. PubMed ID: 29212164), endometrial cancer (Singh et al. 2020. PubMed ID: 32634176), and ovarian cancer (Pal et al. 2012. PubMed ID: 23047549). Functional studies did not support the pathogenicity of this variant (Figure S7, Houlleberghs et al. 2016. PubMed ID: 26951660; LOF score <0 in Table S4, Jia et al. 2021. PubMed ID: 33357406). This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-47710015-T-G) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/91039/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000760996	SCV000890911	uncertain significance	Lynch syndrome	2020-12-02	criteria provided, single submitter	clinical testing	The MSH2 c.2732T>G (p.Leu911Arg) missense change has a maximum subpopulation frequency of 0.013% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/2-47710015-T-G). Six of seven in silico tools predict a damaging effect of this variant on protein function (PP3). However, a functional assay demonstrated that this variant did not result in 6TG-resistant colony formation, an indicator of mismatch repair activity, suggesting a likely benign effect (PMID: 26951660). This variant has been identified in at least four individuals with colon cancer (PMID: 12537652, 18033691, 23047549, 28125075, 29212164), one individual with endometrial cancer (PMID: 32634176), one individual with epithelial ovarian cancer (PMID: 23047549). In one of these studies, the variant did not segregate with the cancer phenotype within the proband’s family (PMID: 18033691). Another report indicates the presence of the variant in 7 individuals in a cancer-free pedigree on both sides of the family with no mention of consanguinity (https://pubmed.ncbi.nlm.nih.gov/26092435/). In summary, this variant meets criteria to be classified as of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589745	SCV001470549	uncertain significance	not provided	2022-07-23	criteria provided, single submitter	clinical testing	This variant has not been described in online databases. The frequency of this variant in the general population, 0.00013 (17/128602 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with endometrial cancer (PMID: 32634176 (2020)), colon cancer (PMID: 29212164 (2017), 28125075 (2017, 12537652 (2002)), and ovarian cancer (PMID: 23047549 (2012)). Although one study observed high microsatellite instability in a tumor and described this variant as deleterious, another study described this variant as benign because of a lack of co-segregation with disease (PMID: 12537652 (2002) and 18033691 (2008)). A mouse embryonic stem cell based functional study reported that this variant does not have a deleterious effect on MMR activity (PMID: 26951660 (2016), 33357406 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Sema4, Sema4	RCV000129717	SCV002534500	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-05	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000235177	SCV002760651	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149751	SCV003837632	uncertain significance	Breast and/or ovarian cancer	2021-07-20	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000172810	SCV004018376	likely benign	Lynch syndrome 1	2023-03-22	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354813	SCV001549518	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH2 p.Leu911Arg variant was identified in 2 of 5650 proband chromosomes (frequency: 0.0004) from individuals or families with lynch syndrome or ovarian cancer and was identified in 1 of 1140 control chromosomes (freq: 0.001), from healthy individuals (Barnetson 2008, Pal 2012, Karageorgos 2015). The variant was also identified in dbSNP (ID: rs41295182) as "With other allele ", ClinVar (classified as uncertain significance by Invitae, GeneDx, Pathway Genomics, Counsyl, InSight and two clinical laboratories; as likely benign by Ambry Genetics), Clinvitae, MutDB, Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors (6x class3). The variant was not identified in the COGR, Cosmic, UMD-LSDB, or Zhejiang University databases. The variant was identified in control databases in 17 of 275962 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 23976 chromosomes (freq: 0.00004), European in 16 of 126192 chromosomes (freq: 0.0001); but not observed in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Leu911 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. This variant is classified as a variant of uncertain significance.