2-47410162-T-G
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4_Moderate
The ENST00000233146.7(MSH2):c.435T>G(p.Ile145Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000295 in 1,614,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I145T) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.00034 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00029 ( 0 hom. )
Consequence
MSH2
ENST00000233146.7 missense
ENST00000233146.7 missense
Scores
1
4
14
Clinical Significance
Conservation
PhyloP100: -0.00500
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 Uncertain_significance. Variant got 0 ACMG points.
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 11 benign, 16 uncertain in ENST00000233146.7
BP4
Computational evidence support a benign effect (MetaRNN=0.1011188).
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MSH2 | NM_000251.3 | c.435T>G | p.Ile145Met | missense_variant | 3/16 | ENST00000233146.7 | NP_000242.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MSH2 | ENST00000233146.7 | c.435T>G | p.Ile145Met | missense_variant | 3/16 | 1 | NM_000251.3 | ENSP00000233146 | P1 |
Frequencies
GnomAD3 genomes 0.000342 AC: 52AN: 152168Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000322 AC: 81AN: 251426Hom.: 0 AF XY: 0.000353 AC XY: 48AN XY: 135882
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GnomAD4 exome AF: 0.000290 AC: 424AN: 1461846Hom.: 0 Cov.: 32 AF XY: 0.000270 AC XY: 196AN XY: 727226
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GnomAD4 genome 0.000341 AC: 52AN: 152286Hom.: 0 Cov.: 31 AF XY: 0.000269 AC XY: 20AN XY: 74468
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:12Benign:14
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:2Benign:3
| 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: Multiple papers classified as non-pathogenic, ExAC: 0.1% (38/66740) European chromosomes - |
| Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Feb 06, 2024 | - - |
| Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 11, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 10, 2023 | Variant summary: MSH2 c.435T>G (p.Ile145Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 251922 control chromosomes, predominantly within the Non-Finnish European subpopulation at a frequency of 0.00049 in the gnomAD database. Both of these frequencies are slightly lower than expected for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (0.00057), allowing no conclusion about variant significance. c.435T>G has been reported in the literature in individuals affected with Nonpolyposis Colorectal Cancer, where co-segregation with the disease was observed in at least two families (e.g., Parc 2003, Spaepen 2006). However, in these studies, not all MMR genes were analyzed and the possibility of other deleterious variants contributing to the disease phenotype cannot be excluded. Some of the reported patients have also carried other MSH6 variants (such as L1354Q; classified as VUS by InSiGHT), and the possibility of compound pathogenicity was suggested by the authors (e.g. Kariola 2003). This variant has been observed in a cohort of breast cancer patients as well as unaffected controls (e.g., Dorling_2021). These reports therefore do not provide unequivocal conclusions about association of the variant with Nonpolyposis Colorectal Cancer. However, a breast cancer patient was reported to carry the variant of interest as well as the variant PALB2 c.38_39insG/p.K14fs*29 (p.K14fs*29; Spugnesi_2016), providing supporting evidence for a benign role. Multiple publications have reported experimental evidence evaluating an impact on protein function, and demonstrated the variant results in preserved MSH2-MSH6 interaction and proficient MMR activity, further supporting a benign classification (e.g., Kariola 2003, Gammie 2007, Kansikas 2011, Kantelinen 2012). Multiple submitters have reported this variant to ClinVar after 2014 with conflicting assessments (VUS, n = 12; likely benign, n = 5; benign, n = 3). Based on the evidence outlined above, the variant was classified as likely benign. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 30, 2016 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2Benign:3
| Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 18, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 05, 2015 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 02, 2020 | 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Mar 12, 2024 | - - |
Lynch syndrome 1 Uncertain:3Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 28, 2017 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Feb 21, 2019 | 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. - |
| Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 22, 2023 | This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease. - |
not provided Uncertain:1Benign:3
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 23, 2021 | This variant is associated with the following publications: (PMID: 32075053, 31159747, 20176959, 26333163, 26096739, 28874130, 26332594, 24040339, 21788563, 17192056, 24933000, 20007843, 27328445, 21120944, 25133505, 12624141, 22581703, 12522549, 17720936, 25637381, 15254659, 16736289, 16451135, 15855432, 30238922) - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | MSH2: BP4 - |
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
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 | Jun 12, 2023 | - - |
MSH2-related disorder Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 06, 2023 | The MSH2 c.435T>G variant is predicted to result in the amino acid substitution p.Ile145Met. This variant has been reported in individuals with hereditary non-polyposis colorectal cancer (Parc et al. 2003. PubMed ID: 12624141; Kariola et al. 2003. PubMed ID: 12522549; Kurzawski et al. 2006. PubMed ID: 16451135) and in one family with suspected Lynch syndrome (Rossi et al. 2017. PubMed ID: 28874130). In at least one case, microsatellite instability (an indicator of defective mismatch repair) and absence of MLH1 protein was also reported along with this variant (Pinol et al. 2005. PubMed ID: 15855432). A second variant in MSH6 was identified in a familial study suggesting digenic inheritance, but neither the MSH2 c.435T>G variant nor the second MSH6 variant impacted mismatch repair (Kariola et al. 2003. PubMed ID: 12522549). An independent functional study in yeast of the MSH2 p.Ile145Met change also revealed no difference in protein activity compared to the wild type (Gammie et al. 2007. PubMed ID: 17720936). This variant has conflicting interpretations in ClinVar, ranging from benign to a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/91097/). This variant is reported in 0.046% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-47637301-T-G). Taken together, we suspect this variant to be benign, although at this time this variant’s clinical significance is uncertain. - |
Breast carcinoma Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5399763:Mismatch repair cancer syndrome 1 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Carcinoma of colon Benign:1
| Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MSH2 p.Ile145Met variant was identified in 2 of 628 proband chromosomes (frequency: 0.003) from individuals or families with hereditary non-polyposis colorectal cancer or renal cell carcinoma (Spaepen 2006, Rubio-Del-Campo 2008). The variant was also identified in dbSBP (ID: rs63750124) classified as “With Uncertain significance”, ClinVar (1x benign: Invitae; 2x likely benign: Ambry Genetics, University of Washington Medical Center; 3x uncertain signirnficance: InSiGHT, GeneDx, Partners HealthCare), UMD-LSDB (biological significance: unclassified/unknown variant), Insight Colon Cancer Gene Variant Database (28 entries, class 3, uncertain significance), Mismatch Repair Genes Variant Database (5 references) databases. The variant was not identified in Genesight-COGR, MutDB, Zhejiang Colon Cancer Database, Insight Hereditary Tumors Database, or COSMIC databases. The variant was identified by our laboratory in 1 individual with endometrial cancer with MSH2/MSH6 deficiency by IHC. The variant was identified in control databases in 82 of 277196 chromosomes at a frequency of 0.0003 in the following populations: European (Non-Finnish) in 57 of 126682 chromosomes (freq. 0.00045), Latino in 12 of 34418 chromosomes (freq. 0.0003), European (Finnish) in 5 of 25792 chromosomes (freq. 0.0002), African in 3 of 24038 chromosomes (freq. 0.0001), and South Asian in 1 of 30782 chromosomes (freq. 0.00003), and other in 4 of 6466 chromosomes (freq. 0.0006) but was not seen in Ashkenazi Jewish and East Asian populations, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). Functional studies using combined co-immunoprecipitation/ Western blot analysis shows this variant combined with wild type MSH6 actually increases protein translation, and the protein demonstrates an increased proportion of the MSH2 component. In addition, a MMR functional assay demonstrates that this variant is as functional as wild type protein, suggesting that, provided that protein levels are adequate, this variant is non-pathogenic (Kariola 2003). A yeast MMR assay demonstrates this variant retains 89% activity relative to wild type, supporting a non-pathogenic classification (Gammie 2007). A review of prior studies finds this variant to be non-pathogenic by MMR assay, in silico analysis, expression and interaction analysis, though it is noted that this variant has been found in carriers of other MMR gene variations (Kansikas 2010). Expression of MSH2 protein is demonstrated to be present by IHC in a non-Amsterdam criteria/non-Bethesda Guidelines patient with this variant (Pinol 2005). The p.Ile145Met residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. This residue is not located in an MSH2-MSH6 interaction region (Wielders 2013). 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. The variant is located within the DNA mismatch repair protein MSH2 functional domain, increasing the likelihood that it may have clinical significance. 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. - |
Lynch syndrome Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 23, 2024 | - - |
Colorectal cancer, non-polyposis Benign:1
| Likely benign, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;T;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;.;.;.
MutationTaster
Benign
D;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;.;N
REVEL
Uncertain
Sift
Benign
D;T;D;.;T
Sift4G
Benign
T;T;T;.;T
Polyphen
B;.;.;.;B
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
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