Submissions for variant NM_000535.7(PMS2):c.746_753del (p.Asp249fs)

dbSNP: rs587782710

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132182	SCV000187261	pathogenic	Hereditary cancer-predisposing syndrome	2014-03-20	criteria provided, single submitter	clinical testing	The c.746_753del8 pathogenic mutation located in coding exon 7 of the PMS2 gene, results from a deletion of 8 nucleotides at nucleotide positions 746 to 753, causing a translational frameshift with a predicted alternate stop codon. This mutation has been reported in a patient with colorectal cancer diagnosed at age 38 (Talseth-Palmer BA et al. Hered Cancer Clin Pract 2010; 8:5). In addition to the clinical data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
Ambry Genetics	RCV000132182	SCV000275106	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-25	criteria provided, single submitter	clinical testing	The c.746_753delACTCCGTG pathogenic mutation, located in coding exon 7 of the PMS2 gene, results from a deletion of 8 nucleotides at nucleotide positions 746 to 753, causing a translational frameshift with a predicted alternate stop codon (p.D249Vfs*2). This mutation has been reported in multiple individuals with a personal and/or family history of HNPCC/Lynch syndrome-associated cancers (Talseth-Palmer BA et al. Hered Cancer Clin Pract, 2010 May;8:5; Yurgelun MB et al. Gastroenterology, 2015 Sep;149:604-13.e20; van der Klift HM et al. Hum Mutat, 2016 11;37:1162-1179; Espenschied CR et al. J Clin Oncol, 2017 Aug;35:2568-2575). This mutation has also been detected in conjunction with a second PMS2 mutation in patients with features consistent with constitutional mismatch repair deficiency (CMMRD) syndrome (Guerrini-Rousseau L et al. Neurooncol Adv Dec;1:vdz033; Ambry internal data). 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.
Invitae	RCV000227297	SCV000285153	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp249Valfs*2) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with colorectal cancer and suspected Lynch syndrome (PMID: 20487569, 25980754, 27064304, 27435373). ClinVar contains an entry for this variant (Variation ID: 142778). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000657186	SCV000778908	pathogenic	not provided	2023-05-12	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Talseth-Palmer et al., 2010; Yurgelun et al., 2015; Goodenberger et al., 2016; Wang et al., 2020); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 20487569, 25856668, 27064304, 28514183, 27435373, 30787465, 31992580, 25980754)
Revvity Omics, Revvity	RCV000657186	SCV003818357	pathogenic	not provided	2022-09-24	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003453094	SCV004187734	pathogenic	Lynch syndrome 4	2023-09-19	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	RCV003453094	SCV004207855	likely pathogenic	Lynch syndrome 4	2023-04-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132182	SCV004359662	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-21	criteria provided, single submitter	clinical testing	This variant deletes 8 nucleotides in exon 7 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 been reported in individuals affected with or suspected of having Lynch syndrome or constitutional mismatch repair deficiency (PMID: 20487569, 25980754, 27064304, 27435373, 32642664). 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000657186	SCV001551689	pathogenic	not provided		no assertion criteria provided	clinical testing	The PMS2 p.Asp249Valfs*2 variant was identified in 3 of 3382 proband chromosomes (frequency: 0.0009) from individuals or families with Lynch syndrome (Talseth-Palmer 2016, van der Klift 2016, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs587782710) as “With Pathogenic allele”, ClinVar and Clinvitae (as pathogenic by Ambry Genetics and Invitae), and Insight Hereditary Tumors Database (4x). The variant was not identified in COGR, Cosmic, MutDB, Zhejiang Colon Cancer Database, or the Mismatch Repair Genes Variant Database. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.746_753del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 249 and leads to a premature stop codon at position 250. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the PMS2 gene are an established mechanism of disease in Lynch syndrome and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.