rs63750086
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000251.3(MSH2):c.1226_1227delAG(p.Gln409fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,790 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
MSH2
NM_000251.3 frameshift
NM_000251.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.44
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 Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-47429890-CAG-C is Pathogenic according to our data. Variant chr2-47429890-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 90577.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47429890-CAG-C is described in Lovd as [Likely_pathogenic]. Variant chr2-47429890-CAG-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MSH2 | NM_000251.3 | c.1226_1227delAG | p.Gln409fs | frameshift_variant | 7/16 | ENST00000233146.7 | NP_000242.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MSH2 | ENST00000233146.7 | c.1226_1227delAG | p.Gln409fs | frameshift_variant | 7/16 | 1 | NM_000251.3 | ENSP00000233146.2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461790Hom.: 0 AF XY: 0.00000413 AC XY: 3AN XY: 727206
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:20
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Lynch syndrome 1 Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | GenePathDx, GenePath diagnostics | Aug 17, 2017 | Diagnosed case of FAP - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 26, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Oct 27, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 02, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 23, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
Lynch syndrome Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 27, 2018 | Variant summary: MSH2 c.1226_1227delAG (p.Gln409ArgfsX7) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 246188 control chromosomes (gnomAD). The variant, c.1226_1227delAG, has been reported in the literature in multiple individuals affected with Lynch Syndrome (Goodfellow_2015, Mangold_2005). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | University of Washington Department of Laboratory Medicine, University of Washington | Nov 20, 2015 | - - |
| Pathogenic, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Sep 05, 2013 | Coding sequence variation introducing a premature termination codon - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 18, 2023 | This variant deletes 2 nucleotides in exon 7 of the MSH2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals affected with Lynch syndrome (PMID: 8872463, 17569143, 25712738, 26552419). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
not provided Pathogenic:5
| Pathogenic, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 04, 2024 | The MSH2 c.1226_1227del (p.Gln409Argfs*7) variant alters the translational reading frame of the MSH2 mRNA and causes the premature termination of MSH2 protein synthesis. This variant has been reported in the published literature in multiple individuals affected with Lynch syndrome-associated cancers including colorectal and endometrial cancers showing loss of MSH2 protein expression and high microsatellite instability (MSI) (PMIDs: 8872463 (1996), 15849733 (2005), 17569143 (2007), 21778331 (2011), 22081473 (2012), 25712738 (2015), 26681312 (2015), 36293153 (2022), 38295319 (2024), 38762859 (2024)). It has also been reported to co-segregate with disease in families (InSiGHT, http://www.insight-database.org). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 02, 2023 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 21778331, 16216036, 8872463, 17569143, 24244552, 19419416, 25712738, 26552419, 29360161, 28874130, 26681312, 30787465, 31692600, 31664942, 31830689, 31948886, 31615790) - |
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | May 25, 2016 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 06, 2023 | This variant deletes 2 nucleotides in exon 7 of the MSH2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals affected with Lynch syndrome (PMID: 8872463, 17569143, 25712738, 26552419). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 04, 2024 | The c.1226_1227delAG pathogenic mutation, located in coding exon 7 of the MSH2 gene, results from a deletion of two nucleotides at nucleotide positions 1226 to 1227, causing a translational frameshift with a predicted alternate stop codon (p.Q409Rfs*7). This alteration has been identified in numerous ethnically diverse individuals/ families with HNPCC/Lynch syndrome (Liu T et al. Genes Chromosomes Cancer. 2000 Jan;27:17-25; Mueller-Koch Y et al. Gut. 2005 Dec;54:1733-40; Lagerstedt Robinson K et al. J. Natl. Cancer Inst. 2007 Feb;99:291-9; Papp J et al. World J Gastroenterol. 2007 May;13:2727-32; Tang R et al. Clin Genet. 2009 Apr;75:334-45; Pérez-Cabornero L et al. Cancer Prev. Res. (Phila). 2011 Oct;4:1546-55; Egoavil C et al. PLoS ONE. 2013 Nov;8:e79737; Siraj AK et al. Cancer. 2015 Jun;121:1762-71; Goodfellow PJ et al. J. Clin. Oncol. 2015 Dec;33:4301-8). Additionally, this alteration has been identified in individuals with pancreatic, prostate, and urinary tract malignancies, as well as sebaceous carcinoma (Dudley B et al. Cancer 2018 Apr;124:1691-1700; Burris CKH et al. Case Rep Ophthalmol. May 2019;10:180-185; Wischhusen JW et al. Cancer Epidemiol Biomarkers Prev. 2020 01;29:193-199; Wu Y et al. Eur Urol Oncol. 2020 04;3:224-230). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
MSH2-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 17, 2024 | The MSH2 c.1226_1227delAG variant is predicted to result in a frameshift and premature protein termination (p.Gln409Argfs*7). This variant has been reported in multiple individuals with Lynch syndrome (see for example, Table 4, Goodfellow et al. 2015. PubMed ID: 26552419; Table 3, Rossi et al. 2017. PubMed ID: 28874130; Table 2, Dudley et al. 2018. PubMed ID: 29360161). This variant has also been reported in multiple individuals with various cancers including endometrial, prostate, and urinary tract cancers (Table 1, Susswein et al. 2015. PubMed ID: 26681312; Table S1, Wu et al. 2020. PubMed ID: 31948886; Table S1, Wischhusen et al. 2019. PubMed ID: 31615790). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been classified as pathogenic by an expert panel in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/90577/). Frameshift variants in MSH2 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Ovarian cyst Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences | Aug 09, 2021 | - - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change creates a premature translational stop signal (p.Gln409Argfs*7) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Lynch syndrome and endometrial cancer (PMID: 8872463, 15849733, 17569143, 19419416, 21778331, 24244552, 26552419, 26845104). ClinVar contains an entry for this variant (Variation ID: 90577). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
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