Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000535.7(PMS2):c.328G>T(p.Ala110Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,442,096 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A110T) 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 Likely_pathogenic. Variant got 6 ACMG points.
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_000535.7
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.889
Uncertain significance, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Apr 06, 2023
This missense variant replaces alanine with serine at codon 110 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 29684080, 35886069). This variant has been identified in 4/235996 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
Dec 09, 2022
The p.A110S variant (also known as c.328G>T), located in coding exon 4 of the PMS2 gene, results from a G to T substitution at nucleotide position 328. The alanine at codon 110 is replaced by serine, an amino acid with similar properties. This alteration has been observed in one individual from a cohort of patients with Cowden/Cowden-like (CS/CS-like) and Bannayan-Riley-Ruvalcaba syndromes (BRRS) without PTEN mutations (Yehia L et al. PLoS Genet., 2018 04;14:e1007352). This alteration was also detected in 2 breast cancer patients from 104 cases of familial cancer in an Italian cohort (Paduano F et al. Genes (Basel), 2022 Jul;13:). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
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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Lynch syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health
May 15, 2023
This missense variant replaces alanine with serine at codon 110 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 29684080, 35886069). This variant has been identified in 4/235996 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. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
GeneDx
Jun 16, 2023
Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer (Yehia et al., 2018; Paduano et al., 2022); This variant is associated with the following publications: (PMID: 35886069, 11574484, 29684080) -
Uncertain significance, criteria provided, single submitter
clinical testing
Invitae
Sep 15, 2023
This variant is present in population databases (rs767775907, gnomAD 0.003%). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 110 of the PMS2 protein (p.Ala110Ser). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. 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. 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. ClinVar contains an entry for this variant (Variation ID: 234814). -
Lynch syndrome 4 Uncertain:1
Uncertain significance, criteria provided, single submitter