ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.853_856ACAG[2] (p.Arg287fs) (rs267608154)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000216774 SCV000276464 pathogenic Hereditary cancer-predisposing syndrome 2018-01-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Color RCV000216774 SCV000686247 pathogenic Hereditary cancer-predisposing syndrome 2016-09-28 criteria provided, single submitter clinical testing
Counsyl RCV000663080 SCV000786157 pathogenic Hereditary nonpolyposis colorectal cancer type 4 2018-03-12 criteria provided, single submitter clinical testing
GeneDx RCV000414373 SCV000490730 pathogenic not provided 2018-03-13 criteria provided, single submitter clinical testing This deletion of four nucleotides in PMS2 is denoted c.861_864delACAG at the cDNA level and p.Arg287SerfsX19 (R287SfsX19) at the protein level. The normal sequence, with the bases that are deleted in braces, is ACAG[ACAG]TTTTTC. The deletion causes a frameshift, which changes an Arginine to a Serine at codon 287, and creates a premature stop codon at position 19 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. PMS2 c.861_864delACAG has been seen in an individual with early onset rectal cancer (Senter 2008) and in a woman with early onset endometrial cancer with loss of PMS2 staining by immunohistochemistry (Moline 2013). We consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000076894 SCV000697395 pathogenic Lynch syndrome 2016-06-07 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.861_864delACAG (p.Arg287Serfs) variant results in a premature termination codon, predicted to cause a truncated or absent PMS2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1021delA, c.1831dupA. c.2186_2187delTC). One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/120952 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). The variant has been reported in affected individuals in the literature, with absent PMS2 protein via IHC and MSI-H tumors. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076894 SCV000108390 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Invitae RCV000524480 SCV000261051 pathogenic Hereditary nonpolyposis colon cancer 2019-01-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg287Serfs*19) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs267608154, ExAC 0.01%). This variant has been reported in the literature in individuals affected with Lynch syndrome-associated cancers (PMID: 18602922, 25980754, 23612316), and pre-symptomatic or symptomatic Lynch syndrome (PMID: 26110232, 27696107). ClinVar contains an entry for this variant (Variation ID: 91375). Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000414373 SCV000691976 pathogenic not provided no assertion criteria provided clinical testing
Mendelics RCV000076894 SCV000838188 pathogenic Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000414373 SCV000888419 pathogenic not provided 2018-05-09 criteria provided, single submitter clinical testing

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