rs200313585
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_000535.7(PMS2):c.180C>G(p.Asp60Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000731 in 1,586,516 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign 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. D60N) has been classified as Likely benign.
Frequency
Consequence
NM_000535.7 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000855 AC: 130AN: 151978Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000915 AC: 229AN: 250142Hom.: 1 AF XY: 0.000879 AC XY: 119AN XY: 135422
GnomAD4 exome AF: 0.000717 AC: 1029AN: 1434538Hom.: 2 Cov.: 26 AF XY: 0.000664 AC XY: 475AN XY: 715236
GnomAD4 genome AF: 0.000855 AC: 130AN: 151978Hom.: 0 Cov.: 32 AF XY: 0.00108 AC XY: 80AN XY: 74226
ClinVar
Submissions by phenotype
not specified Benign:5
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PMS2 p.Asp60Glu variant was identified in 2 of 792 proband chromosomes (frequency: 0.003) from individuals or families with Lynch syndrome (van der Klift 2016). The variant was also identified in the following databases: dbSNP (ID: rs200313585) as "With Likely benign allele", ClinVar (4x likely benign, including review by expert panel InSiGHT, 1x benign), Clinvitae, and Insight Hereditary Tumors Database (6x, likely not pathogenic/little clinical significance). The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, Zhejiang Colon Cancer Database, or the Mismatch Repair Genes Variant Database. The variant was identified in control databases in 271 of 276504 chromosomes (2 homozygous) at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 4 of 24012 chromosomes (freq: 0.0002), Other in 13 of 6456 chromosomes (freq: 0.002), Latino in 2 of 34384 chromosomes (freq: 0.00006), European in 95 of 126292 chromosomes (freq: 0.0008), and Finnish in 157 of 25784 chromosomes (freq: 0.006). The variant was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. A functional study utilizing a cell-free assay found c.180C>G in vitro mismatch repair activity conserved (Drost 2013). Another study investing the splicing pattern of c.180C>G through use of a minigene assay found no aberrant splicing (van der Klift 2015). The p.Asp60 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 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 this variant meets our laboratory's criteria to be classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 24, 2021 | - - |
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 27, 2023 | Variant summary: PMS2 c.180C>G (p.Asp60Glu) results in a conservative amino acid change located in the DNA mismatch repair protein family, N-terminal domain (IPR002099) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00095 in 281538 control chromosomes, predominantly at a frequency of 0.00075 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. However, this data must be interpreted with caution as there is high homology to a pseudogene, which may artificially inflate the allele frequency. c.180C>G has been reported in the literature in individuals affected with Lynch Syndrome or prostate cancer (Grant_2015, van der Klift_2016, Mateo_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Functional studies showed that this variant was not associated with aberrant splicing (van der Klift_2015) and MMR efficiency at 70% of the wild-type levels (Drost_2013). Multiple ClinVar submissions (evaluation after 2014) cite the variant as benign and likely benign. Based on the evidence outlined above, the variant was classified as benign. - |
Benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
not provided Benign:5
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 30, 2020 | This variant is associated with the following publications: (PMID: 26247049, 24027009, 26336887, 27435373) - |
Likely benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2024 | PMS2: BP1, BS3:Supporting - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Hereditary cancer-predisposing syndrome Benign:4
Benign, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Jan 27, 2025 | The missense variant NM_001322014.2(PMS2):c.180C>G (p.Asp60Glu) has been reported to ClinVar as Likely benign with a status of (3 stars) reviewed by expert panel (Variation ID 91315 as of 2025-01-02). There is a small physicochemical difference between aspartic acid and glutamic acid, which is not likely to impact secondary protein structure as these residues share similar properties. The p.Asp60Glu variant is not predicted to disrupt the existing acceptor splice site The p.Asp60Glu missense variant is predicted to be tolerated by both SIFT or PolyPhen2. The glutamic acid residue at codon 60 of PMS2 is present in Domestic goat and 4 other mammalian species. The nucleotide c.180 in PMS2 is not conserved according to a GERP++ and PhyloP analysis of 100 vertebrates. For these reasons, this variant has been classified as Benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 06, 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. - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 09, 2016 | - - |
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 28, 2020 | - - |
Lynch syndrome 4 Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Breast and/or ovarian cancer Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 27, 2019 | - - |
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
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at