rs33946261
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PP3_ModerateBP6_Very_Strong
The NM_000251.3(MSH2):c.138C>G(p.His46Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000441 in 1,606,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).
Frequency
Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00046 ( 0 hom. )
Consequence
MSH2
NM_000251.3 missense
NM_000251.3 missense
Scores
10
7
2
Clinical Significance
Conservation
PhyloP100: 2.26
Genes affected
MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.898
BP6
Variant 2-47403329-C-G is Benign according to our data. Variant chr2-47403329-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 90654.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47403329-C-G is described in Lovd as [Likely_benign]. Variant chr2-47403329-C-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.000217 AC: 33AN: 152252Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000218 AC: 50AN: 229550Hom.: 1 AF XY: 0.000271 AC XY: 34AN XY: 125496
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GnomAD4 exome AF: 0.000465 AC: 676AN: 1454024Hom.: 0 Cov.: 31 AF XY: 0.000443 AC XY: 320AN XY: 722674
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GnomAD4 genome 0.000217 AC: 33AN: 152252Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14AN XY: 74380
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ClinVar
Significance: Likely benign
Submissions summary: Uncertain:5Benign:16Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not specified Uncertain:1Benign:3Other:1
| Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 19, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Mar 04, 2025 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 10, 2023 | 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 28, 2016 | 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. - |
| not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Lynch syndrome 1 Uncertain:1Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Apr 22, 2020 | 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 - |
| Likely benign, criteria provided, single submitter | clinical testing | Mendelics | Feb 27, 2023 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
Lynch syndrome Benign:3
| Likely benign, reviewed by expert panel | curation | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Dec 19, 2018 | Multifactorial likelihood analysis posterior probability <0.05 - |
| Likely benign, criteria provided, single submitter | research | University of Washington Department of Laboratory Medicine, University of Washington | Apr 26, 2018 | 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. - |
| Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 27, 2024 | - - |
Hereditary cancer-predisposing syndrome Benign:3
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 13, 2018 | 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. - |
| Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jun 26, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 03, 2022 | - - |
not provided Uncertain:1Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 14, 2021 | 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) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 02, 2024 | - - |
Breast and/or ovarian cancer Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Dec 09, 2020 | - - |
Colorectal cancer Uncertain:1
| Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
MSH2-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 14, 2023 | 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). - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 03, 2025 | - - |
Malignant tumor of breast Benign:1
| Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | 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. - |
Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5436806:Mismatch repair cancer syndrome 2 Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 25, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;D
REVEL
Pathogenic
Sift
Uncertain
D;.;D
Sift4G
Uncertain
D;.;D
Polyphen
D;.;D
Vest4
MutPred
Loss of catalytic residue at E48 (P = 0.1192);Loss of catalytic residue at E48 (P = 0.1192);Loss of catalytic residue at E48 (P = 0.1192);
MVP
MPC
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at