Submissions for variant NM_000535.7(PMS2):c.1579_1580del (p.Arg527fs)

dbSNP: rs1064793234

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482204	SCV000565402	pathogenic	not provided	2023-08-27	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: 29345684, 31992580, 26681312, 37591735, 30322717)
Ambry Genetics	RCV000566950	SCV000663481	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-13	criteria provided, single submitter	clinical testing	The c.1579_1580delAG pathogenic mutation, located in coding exon 11 of the PMS2 gene, results from a deletion of two nucleotides at nucleotide positions 1579 to 1580, causing a translational frameshift with a predicted alternate stop codon (p.R527Gfs*14). This alteration has been identified in multiple individuals diagnosed with breast, ovarian, colorectal and/or uterine cancer (Susswein LR et al. Genet. Med., 2016 08;18:823-32; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Roberts ME et al. Genet Med, 2018 10;20:1167-1174; Wang Q et al. J Med Genet, 2020 07;57:487-499). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	RCV000699239	SCV000827940	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg527Glyfs*14) 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 0.0009%). This premature translational stop signal has been observed in individual(s) with breast or ovarian cancer (PMID: 26681312, 30322717). ClinVar contains an entry for this variant (Variation ID: 418417). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000566950	SCV000910444	pathogenic	Hereditary cancer-predisposing syndrome	2020-10-18	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides 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. This variant has been reported in one individual each affected with breast cancer (PMID: 26681312) and ovarian cancer (PMID: 30322717). This variant has been identified in 1/251038 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.
Myriad Genetics, Inc.	RCV003449169	SCV004187742	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	RCV003449169	SCV004205402	pathogenic	Lynch syndrome 4	2023-10-08	criteria provided, single submitter	clinical testing