ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.736_741delinsTGTGTGTGAAG (p.Pro246_Pro247delinsCysValTer) (rs267608150)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076885 SCV000108380 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
GeneDx RCV000235196 SCV000149612 pathogenic not provided 2018-03-13 criteria provided, single submitter clinical testing This pathogenic variant is denoted PMS2 c.736_741delCCCCCTinsTGTGTGTGAAG at the cDNA level and p.Pro246CysfsX3 (P246CfsX3) at the protein level. The surrounding sequence is GCTG[delCCCCCT][insTGTGTGTGAAG]AGTG. This variant causes a frameshift, changing a Proline to a Cysteine at codon 246, and creating a premature stop codon at position 3 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.736_741delCCCCCTinsTGTGTGTGAAG, also reported as c.736_741del6ins11, has been published in the literature as a frequently occurring Lynch syndrome mutation (Clendenning 2008).
Ambry Genetics RCV000115703 SCV000217757 pathogenic Hereditary cancer-predisposing syndrome 2019-03-08 criteria provided, single submitter clinical testing
Invitae RCV001201395 SCV000255296 pathogenic Hereditary nonpolyposis colon cancer 2020-01-08 criteria provided, single submitter clinical testing This sequence change deletes 6 nucleotides and inserts 11 nucleotides in exon 7 of the PMS2 mRNA (c.736_741delinsTGTGTGTGAAG), causing a frameshift at codon 246. This creates a premature translational stop signal (p.Pro246Cysfs*3) and is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in individuals and families affected with Lynch syndrome-associated tumors (PMID: 16619239, 24323032, 18178629, 21376568). This variant has been reported as a common cause of Lynch syndrome in individuals with British and Swedish ancestry (PMID: 18178629). It is also known as c.736_741del6ins11 in the literature. ClinVar contains an entry for this variant (Variation ID: 91366). Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). For these reasons, this variant has been classified as Pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000009829 SCV000584108 pathogenic Hereditary nonpolyposis colorectal cancer type 4 2014-12-09 criteria provided, single submitter research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000076885 SCV000592929 pathogenic Lynch syndrome 2014-12-11 criteria provided, single submitter clinical testing
Color RCV000115703 SCV000686231 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000076885 SCV000697382 pathogenic Lynch syndrome 2017-04-21 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.736_741delinsTGTGTGTGAAG (p.Pro246Cysfs) 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.823C>T; p.Gln275X, c.861_864delACAG; p.Arg287fs). One in silico tool predicts a damaging outcome for this variant. The variant of interest is absent in a large, broad control population, ExAC in 120338 control chromosomes. The variant of interest has been reported in multiple affected individuals via publications and it was suggested that it might be a founder mutation in Swedish/Scandinavian populations (Clendenning_JMG_2008, van der Klift_Hum Mutat_2016). In addition, IHC performed on tumors showed selective lack of staining of PMS2. Lastly, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000076885 SCV000731267 pathogenic Lynch syndrome 2019-05-08 criteria provided, single submitter clinical testing The p.Pro246CysfsX3 variant in PMS2 has been reported in the heterozygous state in more than 13 individuals with Lynch Syndrome-associated cancers (Clendenning 2008, Senter 2008, Ward 2013) and in the compound heterozygous state with another loss-of-function PMS2 variant in at least one individual with constitutional mismatch repair deficiency syndrome (Susswein 2015). Data from large population studies is insufficient to assess the frequency of this variant. The p.Pro246CysfsX3 variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 246 and leads to a premature termination codon 3 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the PMS2 gene is an established disease mechanism in individuals with Lynch Syndrome. In addition, this variant was classified as Pathogenic on Sep 5, 2013 by the ClinGen-approved InSiGHT Expert Panel (ClinVar SCV000108380.2). In summary, this variant meets criteria to be classified as pathogenic for Lynch Syndrome in an autosomal dominant manner based upon the predicted impact to the protein and presence in multiple affected individuals. ACMG/AMP criteria applied: PVS1, PS4_Strong.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000009829 SCV000840049 pathogenic Hereditary nonpolyposis colorectal cancer type 4 2018-02-14 criteria provided, single submitter clinical testing This c.736_741delinsTGTGTGTGAAG (p.Pro246Cysfs*3) variant is predicted to result in a premature stop codon and has been reported in multiple individuals with Lynch syndrome-associated tumors (PMID: 16619239, 24323032, 18178629, 21376568). Therefore, c.736_741delinsTGTGTGTGAAG (p.P246Vfs*3) variant in the PMS2 gene is classified as pathogenic.
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000722010 SCV000853183 pathogenic Burkitt lymphoma; Lymphoma 2017-03-07 criteria provided, single submitter clinical testing This is a frameshift alteration in which coding nucleotides 736 through 741 are deleted and replaced with 11 nucleotides. This is predicted to change a Proline to a Cysteine at amino acid codon 246 and shift the reading frame. Classification criteria: PVS1, PS3, PM2.
Fulgent Genetics,Fulgent Genetics RCV000763590 SCV000894429 pathogenic Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 4 2018-10-31 criteria provided, single submitter clinical testing
OMIM RCV000009829 SCV000030050 pathogenic Hereditary nonpolyposis colorectal cancer type 4 2008-06-01 no assertion criteria provided literature only
GenomeConnect, ClinGen RCV000076885 SCV000986945 not provided Lynch syndrome no assertion provided phenotyping only Variant interpretted as pathogenic and reported on 10/17/2018 by GTR ID 500068. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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