Submissions for variant NM_000251.3(MSH2):c.403C>G (p.Leu135Val)

dbSNP: rs193096019

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166792	SCV000217606	benign	Hereditary cancer-predisposing syndrome	2022-08-08	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.
GeneDx	RCV000997136	SCV000292812	likely benign	not provided	2018-11-30	criteria provided, single submitter	clinical testing
Invitae	RCV000546078	SCV000625423	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166792	SCV000685089	likely benign	Hereditary cancer-predisposing syndrome	2023-05-24	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV002053989	SCV002495849	uncertain significance	Lynch syndrome 1; Mismatch repair cancer syndrome 1; Muir-Torré syndrome	2021-03-16	criteria provided, single submitter	clinical testing	MSH2 NM_000251.2 exon 3 p.Leu135Val (c.403C>G): This variant has not been reported in the literature but is present in 0.001% (3/152180) of total alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/2-47410130-C-G?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:187103). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Sema4, Sema4	RCV000166792	SCV002534517	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-13	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267920	SCV002552197	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002291583	SCV002584685	uncertain significance	Lynch syndrome 1	2022-10-03	criteria provided, single submitter	clinical testing	The MSH2 c.403C>G (p.Leu135Val) missense change has a maximum subpopulation frequency of 0.049% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with Lynch syndrome or constitutional mismatch repair deficiency. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002267920	SCV002598589	uncertain significance	not specified	2022-09-22	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.403C>G (p.Leu135Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.9e-05 in 251312 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (9.9e-05 vs 0.00057), allowing no conclusion about variant significance. c.403C>G has been reported in the literature in individuals affected with Breast Cancer as well as in Healthy controls (Dorling_2021). This report does not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Seven ClinVar submitters have assessed the variant since 2014: six classified the variant as uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV002291583	SCV004196180	uncertain significance	Lynch syndrome 1	2023-10-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000997136	SCV004221002	uncertain significance	not provided	2023-03-10	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00049 (15/30614 chromosomes in South Asian subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with breast cancer as well as in a control individual in a large scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH2)). It was also found in control individuals in a colorectal cancer/polyps study (PMID: 30267214 (2018)). 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 deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357296	SCV001552723	uncertain significance	Lynch syndrome		no assertion criteria provided	clinical testing	The MSH2 p.Leu135Val variant was not identified in the literature nor was it identified in the UMD-LSDB database. The variant was identified in dbSNP (ID: rs193096019) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx and Color). The variant was identified in control databases in 26 of 246210 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 33578 chromosomes (freq: 0.00003), European in 9 of 111674 chromosomes (freq: 0.00008), and South Asian in 16 of 30778 chromosomes (freq: 0.0005); it was not observed in the African, Other, Ashkenazi Jewish, East Asian, and Finnish, populations. The p.Leu135 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 1 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. This variant is classified as a variant of uncertain significance.