Early-onset low rectal adenocarcinoma with a pMMR/MSS phenotype in a patient with an analytically confirmed germline pathogenic PMS2 variant: a case report

Mismatch repair (MMR) protein immunohistochemistry (IHC) and microsatellite instability (MSI) testing are central to colorectal cancer treatment stratification and hereditary-risk assessment, but a pMMR/MSS tumour phenotype does not exclude a germline predisposition in selected patients. We report a 41-year-old woman with low rectal adenocarcinoma whose pretreatment biopsy and resection specimen retained MLH1, PMS2, MSH2 and MSH6 expression and whose tumour was microsatellite stable (MSS) with low tumour mutational burden (TMB-L). Tumour-tissue sequencing initially identified the PMS2 frameshift variant NM_000535.7:c.1577del (p.Asp526AlafsTer69; GRCh37/hg19 chr7:6026819delT). A subsequent orthogonal assay using PMS2-specific three-step nested genomic PCR, TA cloning and Sanger sequencing of peripheral-blood DNA confirmed that the variant mapped to PMS2 and supported its germline origin; the clinical laboratory classified the variant as pathogenic using an ACMG/AMP-based interpretation. No dedicated analyses of tumoural PMS2 somatic second-hit events, loss of heterozygosity, copy-number alterations or promoter methylation were performed; therefore, biallelic PMS2 inactivation was not established. Postoperative circulating tumour DNA molecular residual disease was positive, and a left supraclavicular lymph-node biopsy subsequently confirmed metastatic adenocarcinoma consistent with colorectal origin. This case illustrates that pMMR/MSS findings should not be used in isolation to exclude hereditary risk in patients with early-onset disease or other clinical indications for germline assessment. These findings support selective germline assessment in patients with early-onset or otherwise high-risk pMMR/MSS colorectal cancer, but do not justify universal testing or establish that the tumour was caused by PMS2-associated Lynch syndrome.