7-5987573-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000535.7(PMS2):ā€‹c.1192G>Cā€‹(p.Glu398Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,612,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E398G) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 31)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 4.96
Variant links:
Genes affected
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.2153222).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PMS2NM_000535.7 linkuse as main transcriptc.1192G>C p.Glu398Gln missense_variant 11/15 ENST00000265849.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PMS2ENST00000265849.12 linkuse as main transcriptc.1192G>C p.Glu398Gln missense_variant 11/151 NM_000535.7 P3P54278-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152112
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1460110
Hom.:
0
Cov.:
33
AF XY:
0.00000413
AC XY:
3
AN XY:
726450
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000188
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152112
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
74282
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 14, 2024The p.E398Q variant (also known as c.1192G>C), located in coding exon 11 of the PMS2 gene, results from a G to C substitution at nucleotide position 1192. The glutamic acid at codon 398 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthApr 05, 2019- -
Lynch syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthJun 15, 2023- -
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 18, 2023In 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 not expected to disrupt PMS2 protein function. ClinVar contains an entry for this variant (Variation ID: 486923). This missense change has been observed in individual(s) with juvenile hamartomatous polyps (PMID: 27146957). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 398 of the PMS2 protein (p.Glu398Gln). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.077
BayesDel_addAF
Benign
-0.054
T
BayesDel_noAF
Benign
-0.32
CADD
Benign
18
DANN
Uncertain
0.98
DEOGEN2
Benign
0.088
T;.;.;.;.
Eigen
Benign
-0.071
Eigen_PC
Benign
-0.14
FATHMM_MKL
Benign
0.70
D
LIST_S2
Benign
0.65
T;T;.;T;.
M_CAP
Benign
0.038
D
MetaRNN
Benign
0.22
T;T;T;T;T
MetaSVM
Uncertain
-0.28
T
MutationAssessor
Benign
1.9
L;.;.;.;.
MutationTaster
Benign
1.0
D;N;N;N;N
PrimateAI
Benign
0.29
T
PROVEAN
Benign
-0.69
N;N;.;.;.
REVEL
Benign
0.20
Sift
Benign
0.34
T;T;.;.;.
Sift4G
Benign
0.27
T;T;.;.;.
Polyphen
0.90
P;P;.;.;P
Vest4
0.30
MutPred
0.23
Gain of methylation at K394 (P = 0.1499);.;.;.;.;
MVP
0.69
MPC
0.15
ClinPred
0.38
T
GERP RS
5.5
Varity_R
0.079
gMVP
0.38

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1171400724; hg19: chr7-6027204; COSMIC: COSV99764688; API