Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PP3
The NM_000535.7(PMS2):c.349C>A(p.Leu117Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. L117P) 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]
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: Uncertain_significance. The variant received 5 ACMG points.
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 51 uncertain in NM_000535.7
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.773
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000535.7. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
Selected
Gene
Transcript
Tags
HGVSc
HGVSp
Effect
Exon Rank
Protein
UniProt
PMS2
NM_000535.7
MANE Select
c.349C>A
p.Leu117Met
missense
Exon 4 of 15
NP_000526.2
PMS2
NM_001406875.1
c.-136C>A
5_prime_UTR_premature_start_codon_gain
Exon 4 of 15
NP_001393804.1
PMS2
NM_001322015.2
c.-136C>A
5_prime_UTR_premature_start_codon_gain
Exon 4 of 15
NP_001308944.1
Ensembl Transcripts
Selected
Gene
Transcript
Tags
HGVSc
HGVSp
Effect
Exon Rank
Protein
UniProt
PMS2
ENST00000265849.12
TSL:1 MANE Select
c.349C>A
p.Leu117Met
missense
Exon 4 of 15
ENSP00000265849.7
PMS2
ENST00000382321.5
TSL:1
c.349C>A
p.Leu117Met
missense
Exon 4 of 11
ENSP00000371758.4
PMS2
ENST00000406569.8
TSL:1
n.349C>A
non_coding_transcript_exon
Exon 4 of 13
ENSP00000514464.1
Frequencies
GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
0.00
AC:
0
AN:
1406526
Hom.:
0
Cov.:
26
AF XY:
0.00
AC XY:
0
AN XY:
702840
African (AFR)
AF:
0.00
AC:
0
AN:
32706
American (AMR)
AF:
0.00
AC:
0
AN:
44672
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25874
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39396
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85200
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
39222
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4424
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1076240
Other (OTH)
AF:
0.00
AC:
0
AN:
58792
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
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: 455713). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 117 of the PMS2 protein (p.Leu117Met).
The p.L117M variant (also known as c.349C>A), located in coding exon 4 of the PMS2 gene, results from a C to A substitution at nucleotide position 349. The leucine at codon 117 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.