Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3_Moderate
The NM_000535.7(PMS2):c.916G>A(p.Val306Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000127 in 1,577,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. V306E) 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]
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM1
?
PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain in NM_000535.7
PP3
?
PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.851
Uncertain significance, criteria provided, single submitter
clinical testing
GeneDx
Jul 27, 2023
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with colorectal or breast cancer (Hampel et al., 2018; Jiang et al., 2019; Hu et al., 2022); This variant is associated with the following publications: (PMID: 30521064, 29596542, 32980694, 11574484, 35449176) -
Uncertain significance, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
Jan 10, 2018
- -
Uncertain significance, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Jan 11, 2023
The frequency of this variant in the general population, 0.000021 (6/282508 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with colorectal cancer (PMIDs: 30521064 (2019), 29596542 (2018)) and an unspecified Lynch syndrome-associated cancer (PMID: 31391288 (2020)). The variant has also been observed in control individuals in pancreatic and breast cancer screening studies (PMID 32980694 (2020), 33471991 (2021) and LOVD (http://databases.lovd.nl/shared/genes/PMS2)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Mar 17, 2023
This missense variant replaces valine with methionine at codon 306 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 an individual affected with colorectal cancer (PMID: 30521064) and an individual affected with an unspecified cancer (PMID: 31391288). This variant has been identified in 6/282508 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. -
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Nov 23, 2022
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Lynch syndrome 1 Uncertain:1
Uncertain significance, no assertion criteria provided
clinical testing
Ding PR Lab, Sun Yat-sen University Cancer Center
-
- -
Lynch syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health
Nov 30, 2023
This missense variant replaces valine with methionine at codon 306 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 an individual affected with colorectal cancer (PMID: 30521064) and another individual affected with cancer of unspecified type (PMID: 31391288). This variant has been identified in 6/282508 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
Invitae
Jan 03, 2024
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 306 of the PMS2 protein (p.Val306Met). This variant is present in population databases (rs587780063, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 30521064, 31391288, 34326862). ClinVar contains an entry for this variant (Variation ID: 127801). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMS2 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Lynch syndrome 4 Uncertain:1
Uncertain significance, criteria provided, single submitter