2-47429940-A-G
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6
The NM_000251.3(MSH2):c.1275A>G(p.Glu425Glu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000251 in 1,613,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00026 ( 0 hom. )
Consequence
MSH2
NM_000251.3 splice_region, synonymous
NM_000251.3 splice_region, synonymous
Scores
2
Splicing: ADA: 0.9958
2
Clinical Significance
Conservation
PhyloP100: 1.59
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 -1 ACMG points.
BP6
Variant 2-47429940-A-G is Benign according to our data. Variant chr2-47429940-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 90589.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Likely_benign=5, Likely_pathogenic=1, Benign=2}. Variant chr2-47429940-A-G is described in Lovd as [Likely_benign].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.000158 AC: 24AN: 152226Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000115 AC: 29AN: 251138Hom.: 0 AF XY: 0.000110 AC XY: 15AN XY: 135754
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GnomAD4 exome AF: 0.000261 AC: 381AN: 1461414Hom.: 0 Cov.: 32 AF XY: 0.000238 AC XY: 173AN XY: 727058
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GnomAD4 genome 0.000158 AC: 24AN: 152344Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7AN XY: 74504
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:8Benign:7
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:4Benign:3
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 14, 2017 | Variant summary: The MSH2 c.1275A>G (p.Glu425Glu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change in the second to last nucleotide in exon 7.. This variant was found in 12/120260 control chromosomes at a frequency of 0.0000998, predominantly in individuals of European descent (0.00017; 11/65934 chrs). The variant is also observed in gnomAD dataset at slightly higher frequencies (0.00026; 33/126394 European chrs tested). Although these frequencies do not exceed the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683), the variant may be a functional ethnic polymorphism. The variant has been reported in affected individuals in the literaure, including being present in an unaffected family members or a proband as well as absent in three affected family members from two unrelated pedigrees (Pagenstecher_2006, Leongamornlert_2014), showing a lack of segregation with disease. Additionally, the variant was present in affected individuals who carried second pathogenic mutations in other genes related to hereditary cancers (two pathogenic mutations in the MUTYH gene from Pagenstecher_2006; a pathogenic ATM variant from Leongamornlert_BJC_2014; a frameshift variant in AXIN2 gene from Rohlen_2016; and a pathogenic CHEK2 (c.1100delC) variant from internal LCA sample. RT-PCR studies showed the variant to result in a deletion of 48 bp due to activation of a cryptic splice site in exon 7. However, because it was only a partial effect, a considerable amount of full-length transcript can still be synthesized from the mutant allele which may be sufficient for maintaining MMR activity in a cell even in case of a somatic mutation in the normal allele (Pagenstecher_2006); tumors from carriers of this variant showed normal MSI-S and IHC further supportive of a non-pathogenic outcome for this variant. Multiple clinical diagnostic laboratories/reputable databases classified this variant as VUS while others have classified it as VUS/likely benign. Taken together, based on a high preponderance for an alternate molecular basis of disease among reported patients in the literature and our internal co-occurrence data, this variant is classified as benign. - |
| Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 12, 2019 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 30, 2018 | The MSH2 c.1275A>G; p.Glu425Glu variant (rs63751650) is reported in the medical literature in individuals with Lynch syndrome (Mangold 2005, Pagenstecher 2006, Rohlin 2017), however, it was reported to not co-segregate with disease (Pagenstecher 2006). Additionally, this variant was found in an individual with prostate cancer who also carried a pathogenic ATM variant (Leongamornlert 2014). Functional analysis of p.Glu425Glu suggests this variant causes partial exon skipping (Pagenstecher 2006), but the clinical significance of this is uncertain. The p.Glu425Glu variant is reported in ClinVar (Variation ID: 90589), and is found in the general population with an overall allele frequency of 0.01% (35/276878 alleles) in the Genome Aggregation Database. This variant occurs in the second to last nucleotide in exon 7 and computational algorithms predict this variant to slightly weaken the nearby canonical donor splice site (Alamut v.2.10). Based on available information, the clinical significance of the p.Glu425Glu variant is uncertain at this time. REFERENCES Leongamornlert D et al. Frequent germline deleterious mutations in DNA repair genes in familial prostate cancer cases are associated with advanced disease. Br J Cancer. 2014 Mar 18;110(6):1663-72. Mangold E et al. Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer. Int J Cancer. 2005 Sep 20;116(5):692-702. Pagenstecher C et al. Aberrant splicing in MLH1 and MSH2 due to exonic and intronic variants. Hum Genet. 2006 Mar;119(1-2):9-22. Rohlin A et al. Expanding the genotype-phenotype spectrum in hereditary colorectal cancer by gene panel testing. Fam Cancer. 2017 Apr;16(2):195-203. - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 21, 2020 | In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 27601186, 15849733, 21404120, 24728189, 24556621, 24549055, 16341550, 27696107, 32849802, 31332305) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2022 | MSH2: PM2:Supporting, PP3 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 29, 2016 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 17, 2021 | - - |
Hereditary cancer-predisposing syndrome Benign:3
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 08, 2016 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 07, 2019 | 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 | Apr 09, 2021 | - - |
Lynch syndrome 1 Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Department of Medical and Surgical Sciences, University of Bologna | Dec 06, 2024 | The variant satisfied PM2, PP3 and BP6 criteria. We performed transcript analysis which demonstrated its impact on splicing, allowing to add the PS3 criterion and to classify it as Likely Pathogenic - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Polyp of colon Uncertain:1
| Uncertain significance, criteria provided, single submitter | research | CSER _CC_NCGL, University of Washington | Dec 01, 2017 | Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 61 year old female with a history of 5-10 colon polyps and family history of colorectal cancer and/or polyps. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. - |
MSH2-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 10, 2024 | The MSH2 c.1275A>G is a noncoding alteration. This variant has been documented to interfere with normal mRNA splicing, resulting in a partial in-frame deletion of exon 7 of the gene (Pagenstecher et al. 2006. PubMed ID: 16341550). In the same paper, this variant was described in an individual with colorectal cancer, who inherited this variant from a healthy parent (normal colonoscopy at age 80); however the affected siblings (with polyposis) did not carry this variant. In addition, all three affected individuals were later found to be compound heterozygotes for pathogenic variants in MUTYH. Of note, this variant has been reported in multiple individuals with Lynch syndrome (Mangold et al. 2005. PubMed ID: 15849733; Rohlin et al. 2017. PubMed ID: 27696107; Pearlman et al. 2019. PubMed ID: 30877237, Table S1), ovarian cancer (Song et al. 2014. PubMed ID: 24728189, Table S2), breast cancer (Castéra et al. 2014. PubMed ID: 24549055) and also in a prostate cancer patient who harbored another pathogenic variant in a different gene (Leongamornlert et al. 2014. PubMed ID: 24556621). This variant is reported in 0.026% of alleles in individuals of European (non-Finnish) descent in gnomAD and has conflicting interpretations in ClinVar, ranging from benign to a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/90589/). Although we suspect this variant could be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Carcinoma of colon Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MSH2 p.Glu425= variant was identified in 3 of 4626 proband chromosomes (frequency: 0.0006) from Swedish, British and American individuals or families with CRC/CRC phenotypes or ovarian cancer and was not identified in 3056 control chromosomes from healthy individuals (Song 2014, Rohlin 2017). The variant was analysed for RNA expression levels in affected patients and it was found to cause an in-frame deletion of 48 base pairs in exon 7 resulting in partial skipping of exon 7 due to the creation of a cryptic splice site (Pagenstecher 2006). In this study, family testing for APC was negative and the allele was inherited from the healthy mother; in addition, segregation was excluded as the proband and her 2 affected siblings were compound heterozygotes for 2 pathogenic mutations in MUTYH (c.494A>G; p.Y165C and c.1395_1397delGGA; p.Glu466del; Aretz et al., unpublished data). The variant also co-occurred with a pathogenic AXIN2 variant (c.254del/p.Leu85TyrfsX24) in 1 proband with a CRC phenotype (Rohlin 2017). The variant was identified by our laboratory in 1 individual with colon cancer, co-occurring with a pathogenic EPCAM variant c.859-?_945+415+?del. The variant was also identified in dbSNP (ID: rs63751650) as “With Uncertain significance allele”, in ClinVar (classified as uncertain significance, reviewed by an expert panel 2013; likely benign by Invitae and Ambry Genetics, and uncertain significance by InSIGHT, GeneDx, EGL Genetic Diagnostics, Praxis fuer Hamngenetik Tuebingen, Quest Diagnostics Nichols Institute San Juan Capistrano and Mayo Clinic), Clinvitae (5x), UMD-LSDB (5x as neutral), Insight Colon Cancer Gene Variant Database (2x class 3), Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database (2x class 3); it was not identified in the COGR, Cosmic, MutDB, and Zhejiang Colon Cancer Database. The variant was identified in control databases in 35 of 276878 chromosomes at a frequency of 0.0001 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 2 of 24034 chromosomes (freq: 0.00008), European Non-Finnish in 33 of 126394 chromosomes (freq: 0.0003); it was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Glu425= variant is not expected to have clinical significance because it does not result in a change of amino acid. The c.1275A>G variant occurs in the second last base of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing; however, 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 28, 2024 | - - |
Computational scores
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DS_DL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at