ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1454C>A (p.Thr485Lys) (rs1805323)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076810 SCV000108296 no known pathogenicity Lynch syndrome 2013-09-05 reviewed by expert panel research MAF >1%
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000079104 SCV000110973 benign not specified 2018-03-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130906 SCV000185815 benign Hereditary cancer-predisposing syndrome 2014-07-31 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.
Color Health, Inc RCV000130906 SCV000292094 benign Hereditary cancer-predisposing syndrome 2014-11-04 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000079104 SCV000304719 benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000625385 SCV000469732 benign Hereditary nonpolyposis colorectal cancer type 4 2018-01-12 criteria provided, single submitter clinical testing 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282358 SCV000604896 benign none provided 2020-08-11 criteria provided, single submitter clinical testing
Invitae RCV001081087 SCV000625528 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-08 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000079104 SCV000711442 benign not specified 2017-04-20 criteria provided, single submitter clinical testing p.Thr485Lys in exon 11 of PMS2: This variant is not expected to have clinical si gnificance because it has been identified in 35% (3077/8632) of East Asian chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs1805323).
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000625385 SCV000745192 benign Hereditary nonpolyposis colorectal cancer type 4 2017-05-31 criteria provided, single submitter clinical testing
Counsyl RCV000625385 SCV000785345 benign Hereditary nonpolyposis colorectal cancer type 4 2017-07-07 criteria provided, single submitter clinical testing
GeneDx RCV000034616 SCV001899117 benign not provided 2015-03-03 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 28932927, 28347324, 24728327)
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034616 SCV000043428 no known pathogenicity not provided 2012-07-13 no assertion criteria provided research Converted during submission to Benign.
ITMI RCV000079104 SCV000086044 not provided not specified 2013-09-19 no assertion provided reference population
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353499 SCV000592935 benign Endometrial carcinoma no assertion criteria provided clinical testing PMS2, EXON11, c.1454C>A, p. Thr485Lys, Benign (ACMG 5) The c.1454C>A variant was identified in 7 of 338 chromosomes (frequency: 0.021) from individuals or families with HNPCC and Lynch Syndrome exhibiting café-au-lait spots and cancer. (14756672_Thompson_2004, 15256438_Nakagawa_2004, 16472587_Hendriks_2006, 16619239_Clenndening_2006, 17993636_Gururangan_2008, 24027009_Drost_2013) The variant was also identified in dbSNP (ID: rs1805323 ) “With benign allele”, with a minor allele frequency of 0.112(1000 Genomes Project) HGMD, COSMIC, “Mismatch Repair Genes Variant Database”, “InSiGHT Colon Cancer Database”, ClinVar database as a benign variant by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports). The variant was classified as “unclassified” by a clinical laboratory within the Canadian Open Genetics Repository (http://opengenetics.ca/). This variant was identified in the 1000 Genomes Project in 247 of 2178 chromosomes (frequency: 0.113), and in Exome Variant Server project in 350 of 8600 (frequency: 0.041) European American and in 86 of 4406 (frequency: 0.019) African American alleles, increasing the likelihood that this is/may be a low frequency benign variant in certain populations of origin. This variant was identified in the Exome Aggregation Consortium database to have an allele frequency of 0.079. The p.Thr485Lys variant is not expected to have clinical significance because it is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Thr485 residue is not conserved in mammals and the variant amino acid Threonine (Thr) is present in Macaques, increasing the likelihood that this variant does not have clinical significance. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Mayo Clinic Laboratories, Mayo Clinic RCV000079104 SCV000691973 benign not specified no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000079104 SCV001906413 benign not specified no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV000079104 SCV001924426 benign not specified no assertion criteria provided clinical testing

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