Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000535.7(PMS2):c.248T>G(p.Leu83*) variant causes a stop gained, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
PMS2 (HGNC:9122): (PMS1 homolog 2, mismatch repair system component) The protein encoded by this gene is a key component of the mismatch repair system that functions to correct DNA mismatches and small insertions and deletions that can occur during DNA replication and homologous recombination. This protein forms heterodimers with the gene product of the mutL homolog 1 (MLH1) gene to form the MutL-alpha heterodimer. The MutL-alpha heterodimer possesses an endonucleolytic activity that is activated following recognition of mismatches and insertion/deletion loops by the MutS-alpha and MutS-beta heterodimers, and is necessary for removal of the mismatched DNA. There is a DQHA(X)2E(X)4E motif found at the C-terminus of the protein encoded by this gene that forms part of the active site of the nuclease. Mutations in this gene have been associated with hereditary nonpolyposis colorectal cancer (HNPCC; also known as Lynch syndrome) and Turcot syndrome. [provided by RefSeq, Apr 2016]
PMS2 Gene-Disease associations (from GenCC):
Lynch syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Lynch syndrome 4
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
mismatch repair cancer syndrome 1
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Our verdict: Pathogenic. The variant received 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-6003974-A-C is Pathogenic according to our data. Variant chr7-6003974-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 419752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Nov 05, 2021
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:research
ACMG codes:PVS1, PM2, PP5 -
Lynch syndromePathogenic:2
Apr 02, 2019
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
The p.Leu83X variant in PMS2 has not been previously reported in individuals with Lynch syndrome and was absent from large population studies. However, this variant has been reported in ClinVar (Variation ID: 419752). This nonsense variant leads to a premature termination codon at position 83, which is predicted to lead to a truncated or absent protein. Loss of function of the PMS2 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2. -
Jan 08, 2024
All of Us Research Program, National Institutes of Health
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This variant changes 1 nucleotide in exon 3 of the PMS2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with fibroadenoma who had a family history of breast and ovarian cancer (PMID: 33206196). 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. -
not providedPathogenic:2
Jan 25, 2022
Genetic Services Laboratory, University of Chicago
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
Feb 11, 2021
GeneDx
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Nonsense 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 in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with a personal and/or family history of breast/ovarian cancer (Lovejoy 2020); This variant is associated with the following publications: (PMID: 33206196) -
This variant changes 1 nucleotide in exon 3 of the PMS2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with fibroadenoma who had a family history of breast and ovarian cancer (PMID: 33206196). 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. -
Apr 24, 2025
Ambry Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
The c.248T>G (p.L83*) alteration, located in exon 3 (coding exon 3) of the PMS2 gene, consists of a T to G substitution at nucleotide position 248. This changes the amino acid from a leucine (L) to a stop codon at amino acid position 83. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was detected in a 23-year-old African American woman with a family history of breast and ovarian cancers who was diagnosed with fibroadenoma (Lovejoy, 2021). Based on the available evidence, this alteration is classified as pathogenic. -
This sequence change creates a premature translational stop signal (p.Leu83*) 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 variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 419752). For these reasons, this variant has been classified as Pathogenic. -