Submissions for variant NM_000535.7(PMS2):c.1239dup (p.Asp414fs)

dbSNP: rs267608159

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000200079	SCV000253841	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp414Argfs*44) 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 present in population databases (no rsID available, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with constitutional mismatch repair deficiency-associated tumors (PMID: 20205264, 25691505, 26437257). ClinVar contains an entry for this variant (Variation ID: 216072). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000484340	SCV000568205	pathogenic	not provided	2018-11-06	criteria provided, single submitter	clinical testing	This duplication of one nucleotide in PMS2 is denoted c.1239dupA at the cDNA level and p.Asp414ArgfsX44 (D414RfsX44) at the protein level. The normal sequence, with the base that is duplicated in brackets, is GAAAAAAA[dupA]GACG. The duplication causes a frameshift which changes an Aspartic Acid to an Arginine at codon 414, and creates a premature stop codon at position 44 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.1239dupA has been observed in the compound heterozygous state with a nonsense variant in an individual with brain cancer and duodenal cancer diagnosed prior to age 18, consistent with autosomal recessive constitutional mismatch repair deficiency syndrome (Vaughn 2010). This variant was also observed in an individual with early-onset colon cancer and family history meeting Amsterdam Criteria I (Carneiro da Silva 2015). We consider this variant to be pathogenic.
Ambry Genetics	RCV000562604	SCV000663437	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-19	criteria provided, single submitter	clinical testing	The c.1239dupA pathogenic mutation, located in coding exon 11 of the PMS2 gene, results from a duplication of A at nucleotide position 1239, causing a translational frameshift with a predicted alternate stop codon (p.D414Rfs*44). This alteration was detected in conjunction with PMS2 c.1927C>T (p.Gln643X) in a patient diagnosed with a brain tumor at age 14 and a PMS2-deficient duodenal tumor at age 15, which is consistent with a diagnosis of constitutional mismatch repair deficiency syndrome; further, this patient's mother's testing detected the c.1239dupA alteration only (Vaughn CP et al. Hum. Mutat. 2010 May;31:588-93). In a study of Brazilian patients suspected to have Lynch syndrome, this alteration was reported in a patient with colon cancer at age 37, whose family history met Amsterdam I Criteria (Carneiro da Silva F et al. PLoS ONE. 2015 Oct;10:e0139753). 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.
GeneKor MSA	RCV000562604	SCV000821765	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-01	criteria provided, single submitter	clinical testing	This variant consists of 1 nucleotide insertion in exon 11 of the PMS2 mRNA (c.1239dupA), causing a frameshift at codon 414. Consequently, a premature stop codon is created 44 amino acid residues later. This is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMS2 are known to be pathogenic. This variant has been described in the international literature (PMID: 26437257, PMID: 20205264). The mutation database ClinVar contains entries for this variant (Variation ID: 216072/).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000484340	SCV000889609	pathogenic	not provided	2018-02-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000562604	SCV000906644	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-05	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 11 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected of Lynch syndrome (PMID: 26437257). This variant has also been reported in individuals affected with or suspected of constitutional mismatch repair syndrome (PMID: 20205264, 21261604, 25691505). This variant has been identified in 1/31348 chromosomes 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000484340	SCV001446879	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003454499	SCV004187764	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	RCV003454499	SCV004207888	pathogenic	Lynch syndrome 4	2022-07-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987445	SCV004804183	pathogenic	Hereditary nonpolyposis colon cancer	2024-01-05	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1239dupA (p.Asp414ArgfsX44) 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. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.1239dupA has been reported in the literature in individuals affected with suspected Lynch Syndrome (e.g., Carneiro da Silva_2015). The following publication was ascertained in the context of this evaluation (PMID: 26437257). ClinVar contains an entry for this variant (Variation ID: 216072). Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000484340	SCV000691975	pathogenic	not provided		no assertion criteria provided	clinical testing
Gharavi Laboratory, Columbia University	RCV000484340	SCV000809469	pathogenic	not provided	2018-09-16	no assertion criteria provided	research