rs63749910
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3BP6_Very_Strong
The NM_000251.3(MSH2):c.1730T>C(p.Ile577Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000215 in 1,564,106 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 (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I577V) has been classified as Likely benign.
Frequency
Consequence
NM_000251.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH2 | NM_000251.3 | c.1730T>C | p.Ile577Thr | missense_variant | 11/16 | ENST00000233146.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.1730T>C | p.Ile577Thr | missense_variant | 11/16 | 1 | NM_000251.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000164 AC: 25AN: 152210Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000139 AC: 35AN: 250898Hom.: 0 AF XY: 0.000177 AC XY: 24AN XY: 135694
GnomAD4 exome AF: 0.000221 AC: 312AN: 1411896Hom.: 0 Cov.: 25 AF XY: 0.000203 AC XY: 143AN XY: 705500
GnomAD4 genome ? AF: 0.000164 AC: 25AN: 152210Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74366
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:6
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 18, 2020 | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Uncertain significance, no assertion criteria provided | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jul 13, 2012 | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 06, 2020 | This variant is associated with the following publications: (PMID: 27958275, 22703879, 16636019, 19117025, 22006311, 16736289, 16885385, 21056691, 25871441, 16408224, 26878173, 26182300) - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 23, 2023 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MSH2 p.Ile577Thr variant was identified in 6 of 1950 proband chromosomes (frequency: 0.003) from individuals or families with endometrial, colorectal, and ovarian cancer (Hampel 2006, Limburg 2011, South 2009, Spaepen 2006, Walsh 2011), and was present in 1 of 1142 control chromosomes (frequency: 0.0009) from healthy individuals (Johnston 2012). The variant was also identified in dbSNP (ID: rs63749910) as “With Uncertain significance allele”, ClinVar (as likely benign, reviewed by expert panel and Ambry Genetics, and as uncertain significance by GeneDx, Invitae, Knight Diagnostics, Laboratory for Molecular Medicine, Quest Diagnostics, Integrated Genetics, and Biesecker Lab), Clinvitae (6x), UMD-LSDB (1x as uncertain significance), Insight Colon Cancer Gene Variant Database (5x as "class 2 likely not pathogenic"), and Mismatch Repair Genes Variant Database (1x). The variant was not identified in COGR, Cosmic, MutDB, or Zhejiang University Database. The variant was identified in control databases in 41 of 276890 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 24008 chromosomes (freq: 0.00008), Other in 1 of 6458 chromosomes (freq: 0.0002), Latino in 1 of 34416 chromosomes (freq: 0.00003), and European (Non-Finnish) in 37 of 126452 chromosomes (freq: 0.0003); it was not observed in the Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. One study reported the variant was found to co-occur with a pathogenic MUTYH variant: c.36+1G>A (Niessen 2006). The p.Ile577 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. - |
not specified Uncertain:2Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 07, 2021 | Variant summary: MSH2 c.1730T>C (p.Ile577Thr) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) 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 0.00015 in 251570 control chromosomes, predominantly at a frequency of 0.00028 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (0.00015 vs 0.00057), allowing no conclusion about variant significance. c.1730T>C has been reported in the literature in individuals affected with colorectal cancer, endometrial cancer, ovarian cancer and hereditary diffuse gastric cancer (Spaepen_2006, Niessen_2006, Limburg_2011, Hampel_2006, South_2009, Hansford_2015) without strong evidence of causality. Many of these tumors show normal MSH2 expression by immunohistochemistry. In one patient absence of MLH1 (but normal expression of MSH2) protein was seen together with methylation of MLH1 promoter region suggestive of an alternative etiology and molecular basis of disease in this patient (Hampel_2006). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. At-least two co-occurrences with other pathogenic variant(s) have been reported in the literature and also observed at our laboratory ( MUTYH c.36+1G>A, Niessen_2006; BRCA1 c.3005delA , p.Asn1002fsX22 at our laboratory), providing supporting evidence for a benign role. A study that computed a tumor characteristic likelihood ratio (TCLR) in combination with in-silico predictors and multifactorial variant prediction (MVP) model including allele frequency, co-occurrence, co-segregation, clinical and family history information classified this variant a benign (Li_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign/benign, n=4; VUS, n=5). Based on the evidence outlined above, the variant was classified as benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 25, 2017 | 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: Classified within the last year. This variant has been reported in 1 indidivual who did not have cancer, and 1 individual with CRC. The variant has a Max MAF of 0.02% in ExAC (14 alleles) and 0.03% in gnomAD (38 alleles). It is classified with 3 stars in ClinVar as Likely benign by an expert panel (InSiGHT) and Ambry, and VUS by GeneDx, Invitae, and Biesecker lab. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 16, 2019 | DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.1730T>C, in exon 11 that results in an amino acid change, p.Ile577Thr. This sequence change has been described previously in individuals with colorectal cancer, ovarian cancer or adenocarcinoma of the endometrium (PMID: 21056691, PMID: 19117025, PMID: 16885385, PMID: 16736289). It has been described in the gnomAD database with a low population frequency of 0.029% in non-Finnish European subpopulation (dbSNP rs63749910). The p.Ile577Thr change affects a moderately conserved amino acid residue located in a domain of the MSH2 protein that is known to be functional. The p.Ile577Thr substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these evidences and the lack of functional studies, the clinical significance of the p.Ile577Thr change remains unknown at this time. - |
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 02, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 20, 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 19, 2021 | - - |
Lynch syndrome 1 Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Mar 30, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 16, 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. - |
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 | Mar 02, 2021 | - - |
MSH2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 12, 2021 | 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 colon cancer Benign:1
Benign, criteria provided, single submitter | clinical testing | Mendelics | Aug 22, 2023 | - - |
Lynch syndrome Benign:1
Likely benign, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Sep 05, 2013 | Multifactorial likelihood analysis posterior probability 0.001-0.049 - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at