Submissions for variant NM_000535.7(PMS2):c.1067del (p.Lys356fs)

dbSNP: rs587781395

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129239	SCV000183997	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-23	criteria provided, single submitter	clinical testing	The c.1067delA pathogenic mutation, located in coding exon 10 of the PMS2 gene, results from a deletion of one nucleotide at nucleotide position 1067, causing a translational frameshift with a predicted alternate stop codon (p.K356Rfs*4). This alteration has been reported in multiple individuals with a personal history of colorectal or endometrial cancer (Cragun D et al. Clin. Genet., 2014 Dec;86:510-20; Rosty C et al. BMJ Open, 2016 Feb;6:e010293; Yurgelun MB et al. J. Clin. Oncol., 2017 Apr;35:1086-1095; 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.
GeneDx	RCV000486460	SCV000566328	pathogenic	not provided	2022-06-17	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); 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: 26895986, 24763289, 25856668, 24506336, 28135145)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002514715	SCV003439527	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys356Argfs*4) 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 (rs587781395, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 30608896). ClinVar contains an entry for this variant (Variation ID: 140957). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330500	SCV004038403	pathogenic	Hereditary nonpolyposis colon cancer	2023-08-08	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1067delA (p.Lys356ArgfsX4) 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 variant allele was found at a frequency of 4e-06 in 251214 control chromosomes. c.1067delA has been reported in the literature in individuals affected with PMS2-deficient colorectal cancer and/or Lynch Syndrome (e.g. Rosty_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 26895986). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV003453061	SCV004187663	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	RCV003453061	SCV004205478	pathogenic	Lynch syndrome 4	2023-08-23	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV004556740	SCV005045769	pathogenic	Lynch syndrome	2022-08-15	criteria provided, single submitter	clinical testing	The c.1067del (p.Lys356Argfs*4) variant in the PMS2 is located on exon 10 and is predicted to cause reading frame shift that introduces a premature translation termination codon (p.Lys356Argfs*4), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with Lynch syndrome-associated cancer (PMID: 28135145, 24506336, 30608896, 29345684). Other frameshift/truncation variants located upstream and downstream to this position in the same exon have been reported in individuals with Lynch syndrome-associated cancer and curated as pathogenic (ClinVar ID: 9240, 91289). Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 28514183, 25512458, 35223509). The variant is reported in ClinVar (ID: 140957). The variant is rare in the general population according to gnomAD (1/251214 chromosomes). Therefore, the c.1067del (p.Lys356Argfs*4) variant in the PMS2 gene has been classified as pathogenic