Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000535.7(PMS2):c.2380C>T(p.Pro794Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,454,704 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P794A) has been classified as Uncertain significance.
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]
Uncertain significance, criteria provided, single submitter
clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Feb 06, 2024
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Uncertain significance, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Jun 21, 2022
Variant summary: PMS2 c.2380C>T (p.Pro794Ser) results in a non-conservative amino acid change located in the MutL, C-terminal, dimerisation domain (IPR014790) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 247958 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no confirmed occurrence of c.2380C>T as originating in the PMS2 gene and not the PMS2CL pseudogene in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Although this variant has been reported in the literature in at-least two individuals with familial colorectal cancer who demonstrated MSHI-high tumor and normal IHC staining for MLH1, MSH2, MSH6 and PMS2 proteins, the sequencing methodology employed precludes unequivocal interpretation of this finding in the context of the PMS2 gene and is therefore not weighted in the context of this evaluation (example, Liccardo_2019). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Apr 27, 2023
This missense variant replaces proline with serine at codon 794 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with colorectal cancer whose tumors showed normal expression of PMS2, MLH1, MSH2 and MSH6 (PMID: 31410062). This variant has been identified in 2/247772 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter
clinical testing
Ambry Genetics
Jul 25, 2023
The p.P794S variant (also known as c.2380C>T), located in coding exon 14 of the PMS2 gene, results from a C to T substitution at nucleotide position 2380. The proline at codon 794 is replaced by serine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Lynch syndrome 4 Uncertain:2
Uncertain significance, criteria provided, single submitter
clinical testing
Myriad Genetics, Inc.
Apr 04, 2023
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, criteria provided, single submitter
clinical testing
Counsyl
Jul 06, 2017
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Breast and/or ovarian cancer Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
May 30, 2022
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Lynch syndrome 4;C5399763:Mismatch repair cancer syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Fulgent Genetics, Fulgent Genetics
Oct 31, 2018
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not provided Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
GeneDx
Aug 13, 2021
Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with Lynch syndrome (Liccardo 2019); This variant is associated with the following publications: (PMID: 21552516, 31410062, 31258848) -