rs876659030

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_000535.7(PMS2):​c.2381C>T​(p.Pro794Leu) variant causes a missense change involving the alteration of a 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 (★).

Frequency

Genomes: not found (cov: 30)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

PMS2
NM_000535.7 missense

Scores

10
6
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.99
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.838

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PMS2NM_000535.7 linkc.2381C>T p.Pro794Leu missense_variant Exon 14 of 15 ENST00000265849.12 NP_000526.2 P54278-1Q7Z3Q2B4DGM0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PMS2ENST00000265849.12 linkc.2381C>T p.Pro794Leu missense_variant Exon 14 of 15 1 NM_000535.7 ENSP00000265849.7 P54278-1

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
6.87e-7
AC:
1
AN:
1454634
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
723662
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:
0.00
Gnomad4 NFE exome
AF:
9.04e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
30

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1
Jun 22, 2020
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.P794L variant (also known as c.2381C>T), located in coding exon 14 of the PMS2 gene, results from a C to T substitution at nucleotide position 2381. The proline at codon 794 is replaced by leucine, an amino acid with similar properties. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.26
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.19
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.26
T;.;.;.;.;.
Eigen
Pathogenic
0.91
Eigen_PC
Pathogenic
0.89
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D;.;D;.;D
M_CAP
Uncertain
0.23
D
MetaRNN
Pathogenic
0.84
D;D;D;D;D;D
MetaSVM
Uncertain
0.15
D
MutationAssessor
Uncertain
2.6
M;.;.;.;.;.
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-8.0
D;D;.;.;.;D
REVEL
Pathogenic
0.67
Sift
Uncertain
0.0020
D;D;.;.;.;D
Sift4G
Uncertain
0.0020
D;D;.;.;.;T
Polyphen
0.94
P;D;.;.;D;D
Vest4
0.87
MutPred
0.60
Loss of disorder (P = 0.0436);.;.;.;.;.;
MVP
0.93
MPC
3.3
ClinPred
1.0
D
GERP RS
5.8
Varity_R
0.85
gMVP
0.73

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-6017283; API