rs1805318
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_000535.7(PMS2):c.1789A>T(p.Thr597Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.014 in 1,614,142 control chromosomes in the GnomAD database, including 207 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T597A) has been classified as Uncertain significance.
Frequency
Consequence
NM_000535.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PMS2 | NM_000535.7 | c.1789A>T | p.Thr597Ser | missense_variant | 11/15 | ENST00000265849.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PMS2 | ENST00000265849.12 | c.1789A>T | p.Thr597Ser | missense_variant | 11/15 | 1 | NM_000535.7 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00890 AC: 1354AN: 152204Hom.: 10 Cov.: 32
GnomAD3 exomes AF: 0.00828 AC: 2083AN: 251444Hom.: 13 AF XY: 0.00845 AC XY: 1148AN XY: 135906
GnomAD4 exome AF: 0.0145 AC: 21181AN: 1461820Hom.: 197 Cov.: 32 AF XY: 0.0142 AC XY: 10337AN XY: 727214
GnomAD4 genome ? AF: 0.00891 AC: 1357AN: 152322Hom.: 10 Cov.: 32 AF XY: 0.00832 AC XY: 620AN XY: 74476
ClinVar
Submissions by phenotype
not specified Benign:9Other:1
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Likely benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
Benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 11, 2013 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 24, 2014 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Lynch syndrome 4 Benign:6
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | Jun 20, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Mar 07, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Counsyl | Jun 01, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 24, 2018 | 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. - |
Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | May 11, 2023 | This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. - |
Hereditary cancer-predisposing syndrome Benign:4
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, no assertion criteria provided | clinical testing | True Health Diagnostics | Jan 12, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Vantari Genetics | Feb 04, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 21, 2014 | - - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 17, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | PMS2: BP4, BS1, BS2 - |
Benign, no assertion criteria provided | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jul 13, 2012 | - - |
Lynch syndrome 1 Benign:2
Benign, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Oct 10, 2014 | MAF >1% - |
Likely benign, no assertion criteria provided | clinical testing | Pathway Genomics | Jul 24, 2014 | - - |
Carcinoma of colon Benign:1
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PMS2 p.Thr597Ser variant was identified in 27 of 746 proband chromosomes (frequency: 0.036) from Dutch, American, British and French individuals or families with HNPCC, early-onset CRC, MAP or breast cancer and was identified in 37 of 1922 chromosomes (frequency: 0.02) from healthy individuals (Hendriks 2006, Balogh 2006, Lefevre 2012). The variant was also identified in dbSNP (ID: rs1805318) as "With Likely benign allele", ClinVar (classified 10x as benign: InSiGHT, Invitae, GeneDx, Ambry Genetics, Emory Genetics Laboratory, Vantari Genetics, PreventionGenetics, Counsyl, Color Genomics, Biesecker Lab/NIH; 1x likely benign: Pathway Genomics; 1x not provided: ITMI), Clinvitae (7x), MutDB (UniProt Category: Polymorphism), Insight Colon Cancer Gene Variant Database (12x not pathogenic), and the Mismatch Repair Genes Variant Database (3x). The variant was not identified in GeneInsight-COGR, COSMIC, Zhejiang Colon Cancer Database, or the Insight Hereditary Tumors Database. The variant was identified in control databases in 2380 of 277222 chromosomes (15 homozygous) at a frequency of 0.009 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: European (Non-Finnish) in 1893 of 126716 chromosomes (freq: 0.015) Functional data suggest conflicting effects for this variant. An in vitro pull-down assay demonstrating that this SNP results in defective protein-protein interaction with MLH1, despite the fact that the alteration is outside the putative MLH1 interaction domain, suggests an increased risk factor for tumourigenesis in HNPCC. However, a cell-free MMR functional assay of VUS in PMS2 using MLH1/PMS2 heterodimer to restore a plasmid restriction enzyme site demonstrated 70% activity and was not considered MMR-deficient relative to known pathogenic controls. The p.Thr597Ser residue is not conserved in mammals and 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. - |
Lynch syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | - - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at