chr7-5986753-C-T
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_000535.7(PMS2):βc.2006+6G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0555 in 1,573,106 control chromosomes in the GnomAD database, including 5,348 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (β β β ).
Frequency
Genomes: π 0.052 ( 521 hom., cov: 32)
Exomes π: 0.056 ( 4827 hom. )
Consequence
PMS2
NM_000535.7 splice_donor_region, intron
NM_000535.7 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.00007389
2
Clinical Significance
Conservation
PhyloP100: 0.219
Genes affected
PMS2 (HGNC:9122): (PMS1 homolog 2, mismatch repair system component) The protein encoded by this gene is a key component of the mismatch repair system that functions to correct DNA mismatches and small insertions and deletions that can occur during DNA replication and homologous recombination. This protein forms heterodimers with the gene product of the mutL homolog 1 (MLH1) gene to form the MutL-alpha heterodimer. The MutL-alpha heterodimer possesses an endonucleolytic activity that is activated following recognition of mismatches and insertion/deletion loops by the MutS-alpha and MutS-beta heterodimers, and is necessary for removal of the mismatched DNA. There is a DQHA(X)2E(X)4E motif found at the C-terminus of the protein encoded by this gene that forms part of the active site of the nuclease. Mutations in this gene have been associated with hereditary nonpolyposis colorectal cancer (HNPCC; also known as Lynch syndrome) and Turcot syndrome. [provided by RefSeq, Apr 2016]
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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=-0.71).
BP6
Variant 7-5986753-C-T is Benign according to our data. Variant chr7-5986753-C-T is described in ClinVar as [Benign]. Clinvar id is 91324.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-5986753-C-T is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.325 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PMS2 | NM_000535.7 | c.2006+6G>A | splice_donor_region_variant, intron_variant | ENST00000265849.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PMS2 | ENST00000265849.12 | c.2006+6G>A | splice_donor_region_variant, intron_variant | 1 | NM_000535.7 | P3 |
Frequencies
GnomAD3 genomes AF: 0.0516 AC: 7834AN: 151924Hom.: 520 Cov.: 32
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GnomAD3 exomes AF: 0.0760 AC: 17203AN: 226258Hom.: 1548 AF XY: 0.0797 AC XY: 9795AN XY: 122938
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GnomAD4 exome AF: 0.0559 AC: 79399AN: 1421062Hom.: 4827 Cov.: 28 AF XY: 0.0583 AC XY: 41171AN XY: 706020
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GnomAD4 genome AF: 0.0516 AC: 7840AN: 152044Hom.: 521 Cov.: 32 AF XY: 0.0559 AC XY: 4157AN XY: 74328
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ClinVar
Significance: Benign
Submissions summary: Benign:17
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not specified Benign:6
Benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 21, 2018 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Lynch syndrome 4 Benign:4
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 05, 2023 | This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. - |
Benign, criteria provided, single submitter | clinical testing | Counsyl | Jul 07, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | May 31, 2017 | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | This variant is associated with the following publications: (PMID: 24710284) - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 21, 2023 | - - |
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 | Dec 10, 2014 | - - |
Lynch syndrome Benign:1
Benign, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Sep 05, 2013 | MAF >1% - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Endometrial carcinoma Benign:1
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | Γ’β¬Ε‘ΓβΓΒΊThe PMS2, c.2006+6G>A variant was identified in 7% of 253542 control alleles in the Genome Aggregation Consortium (February 27, 2017). According to ACMG guidelines for variant classification based on allele frequency, category BA1, this variant is considered benign and has not been further reviewed (Richards 2015).Γ’β¬Ε‘ΓβΓΒΉ - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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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