rs17218356
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The ENST00000233146.7(MSH2):c.1662-9G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,341,742 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).
Frequency
Genomes: 𝑓 0.0046 ( 3 hom., cov: 32)
Exomes 𝑓: 0.00063 ( 8 hom. )
Consequence
MSH2
ENST00000233146.7 splice_polypyrimidine_tract, intron
ENST00000233146.7 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.00006028
2
Clinical Significance
Conservation
PhyloP100: 0.975
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 Benign. Variant got -20 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.54).
BP6
Variant 2-47470956-G-A is Benign according to our data. Variant chr2-47470956-G-A is described in ClinVar as [Benign]. Clinvar id is 90730.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47470956-G-A is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0046 (700/152108) while in subpopulation AFR AF= 0.0145 (603/41488). AF 95% confidence interval is 0.0136. There are 3 homozygotes in gnomad4. There are 326 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 3 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MSH2 | NM_000251.3 | c.1662-9G>A | splice_polypyrimidine_tract_variant, intron_variant | ENST00000233146.7 | NP_000242.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.1662-9G>A | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000251.3 | ENSP00000233146 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00461 AC: 700AN: 151990Hom.: 3 Cov.: 32
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GnomAD3 exomes AF: 0.00133 AC: 332AN: 249892Hom.: 2 AF XY: 0.00110 AC XY: 149AN XY: 135284
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GnomAD4 exome AF: 0.000634 AC: 754AN: 1189634Hom.: 8 Cov.: 17 AF XY: 0.000580 AC XY: 351AN XY: 605536
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GnomAD4 genome AF: 0.00460 AC: 700AN: 152108Hom.: 3 Cov.: 32 AF XY: 0.00438 AC XY: 326AN XY: 74354
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ClinVar
Significance: Benign
Submissions summary: Uncertain:2Benign:16
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not specified Uncertain:1Benign:5
Uncertain significance, no assertion criteria provided | research | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 17, 2017 | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
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 | Genetic Services Laboratory, University of Chicago | Nov 28, 2018 | - - |
Lynch syndrome 1 Uncertain:1Benign:3
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | Sep 07, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Hereditary cancer-predisposing syndrome Benign:2
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 18, 2014 | This alteration is classified as 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. - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 18, 2015 | - - |
Breast and/or ovarian cancer Benign:1
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Nov 09, 2021 | - - |
Carcinoma of colon Benign:1
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MSH2 c.1662-9G>A variant was identified in 3 of 584 proband chromosomes (frequency: 0.005) from individuals or families with colorectal cancer (Montera 2000, Farrington 1998, Thompson 2013). The variant was also identified in dbSNP (ID: rs17218356) as “With other allele”, ClinVar (classified as benign by an InSiGHT expert panel (2013) and five other submitters; as likely benign by 2 submitters; and as uncertain significance by 2 submitters). The variant was not identified in UMD-LSDB. The variant was also identified in control databases in 465 (4 homozygous) of 276212 chromosomes at a frequency of 0.002, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 386 (4 homozygous) of 23980 chromosomes (freq: 0.02), Other in 14 of 6450 chromosomes (freq: 0.002), Latino in 38 of 34372 chromosomes (freq: 0.001), European Non-Finnish in 22 of 126108 chromosomes (freq: 0.0002), East Asian in 2 of 18846 chromosomes (freq: 0.0001), and South Asian in 3 of 30556 chromosomes (freq: 0.0001), while it was not observed in the Ashkenazi Jewish or European Finnish populations. The c.1662-9G>A variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions, although positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. However, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. Furthermore, in vitro splicing analysis performed by Thompson (2013) determined the splicing of this allele to be similar to wild type. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. - |
Lynch syndrome Benign:1
Benign, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Sep 05, 2013 | Multifactorial likelihood analysis posterior probability <0.001 - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at