ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1789A>T (p.Thr597Ser) (rs1805318)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000144655 SCV000108314 benign Lynch syndrome I 2014-10-10 reviewed by expert panel research MAF >1%
Invitae RCV001080576 SCV000153971 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-08 criteria provided, single submitter clinical testing
GeneDx RCV000121842 SCV000171034 benign not specified 2013-11-11 criteria provided, single submitter clinical testing 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.
Ambry Genetics RCV000129319 SCV000184082 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000121842 SCV000225236 benign not specified 2014-06-24 criteria provided, single submitter clinical testing
Vantari Genetics RCV000129319 SCV000267072 benign Hereditary cancer-predisposing syndrome 2016-02-04 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000121842 SCV000304724 benign not specified criteria provided, single submitter clinical testing
Counsyl RCV000412079 SCV000488727 benign Hereditary nonpolyposis colorectal cancer type 4 2016-06-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129319 SCV000537366 benign Hereditary cancer-predisposing syndrome 2014-11-21 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000412079 SCV000743778 likely benign Hereditary nonpolyposis colorectal cancer type 4 2016-03-07 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282352 SCV001156611 benign none provided 2020-07-24 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000412079 SCV001326299 likely benign Hereditary nonpolyposis colorectal cancer type 4 2018-01-24 criteria provided, single submitter clinical testing 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.
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034622 SCV000043421 no known pathogenicity not provided 2012-07-13 no assertion criteria provided research Converted during submission to Benign.
ITMI RCV000121842 SCV000086040 not provided not specified 2013-09-19 no assertion provided reference population
Pathway Genomics RCV000144655 SCV000189982 likely benign Lynch syndrome I 2014-07-24 no assertion criteria provided clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000121842 SCV000691966 likely benign not specified no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000412079 SCV000745838 benign Hereditary nonpolyposis colorectal cancer type 4 2016-06-20 no assertion criteria provided clinical testing
True Health Diagnostics RCV000129319 SCV000788110 benign Hereditary cancer-predisposing syndrome 2018-01-12 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357844 SCV001553433 benign Carcinoma of colon no assertion criteria provided clinical testing 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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000121842 SCV001798033 benign not specified no assertion criteria provided clinical testing

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