Submissions for variant NM_000535.7(PMS2):c.1076dup (p.Leu359fs)

dbSNP: rs267608156

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076794	SCV000108276	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000569722	SCV000676163	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-09	criteria provided, single submitter	clinical testing	The c.1076dupT pathogenic mutation, located in coding exon 10 of the PMS2 gene, results from a duplication of T at nucleotide position 1076, causing a translational frameshift with a predicted alternate stop codon (p.L359Ffs*6). This alteration (designated c.1076_1077insT) was reported in an individual diagnosed with endometrial cancer showing loss of PMS2 expression at age 49 and also with colon cancer at age 57 (Senter L et al. Gastroenterology 2008 Aug;135:419-28). This mutation has also been identified in other affected and unaffected individuals with Lynch syndrome (Goodenberger ML et al. Genet. Med. 2016 Jan;18:13-9). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226187	SCV000697277	pathogenic	Hereditary nonpolyposis colon cancer	2023-03-15	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1076dupT (p.Leu359PhefsX6) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant was absent in 251064 control chromosomes (gnomAD). c.1076dupT has been reported in the literature in at least three individuals affected with Lynch Syndrome-associated cancers, including at least one individual with a personal and family history of Lynch Syndrome-associated cancers and a loss of PMS2 determined by immunohistochemistry (e.g. Senter_2008, Goodenberger_2015, Lowery_2018, ten Broeke_2018). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000629951	SCV000750907	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-12-20	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 91289). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 18602922, 23012243). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu359Phefs*6) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816).
GeneDx	RCV000657182	SCV000778903	pathogenic	not provided	2017-06-26	criteria provided, single submitter	clinical testing	This duplication of one nucleotide in PMS2 is denoted c.1076dupT at the cDNA level and p.Leu359PhefsX6 (L359FfsX6) at the protein level. The normal sequence, with the base that is duplicated in brackets, is TCTT[dupT]GATA. The duplication causes a frameshift which changes a Leucine to a Phenylalanine at codon 359, and creates a premature stop codon at position 6 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.1076dupT has been observed in at least three individuals with a personal history of colon and/or endometrial cancer (Senter 2008, Goodenberger 2016). We consider this variant to be pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000569722	SCV000905474	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 10 of the PMS2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000657182	SCV001249107	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	PMS2: PVS1, PM2
MGZ Medical Genetics Center	RCV002288574	SCV002580052	pathogenic	Lynch syndrome 4	2022-03-23	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002288574	SCV004187716	pathogenic	Lynch syndrome 4	2023-09-20	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV002288574	SCV004207828	pathogenic	Lynch syndrome 4	2023-05-28	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000657182	SCV004243285	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing