7-5987336-A-T

Variant summary

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

The NM_000535.7(PMS2):​c.1429T>A​(p.Ser477Thr) 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 benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

PMS2
NM_000535.7 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.747
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.069359034).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PMS2NM_000535.7 linkuse as main transcriptc.1429T>A p.Ser477Thr missense_variant 11/15 ENST00000265849.12 NP_000526.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PMS2ENST00000265849.12 linkuse as main transcriptc.1429T>A p.Ser477Thr missense_variant 11/151 NM_000535.7 ENSP00000265849 P3P54278-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
40
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 05, 2023ClinVar contains an entry for this variant (Variation ID: 455653). 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 not expected to disrupt PMS2 protein function. 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 serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 477 of the PMS2 protein (p.Ser477Thr). -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 04, 2022The p.S477T variant (also known as c.1429T>A), located in coding exon 11 of the PMS2 gene, results from a T to A substitution at nucleotide position 1429. The serine at codon 477 is replaced by threonine, an amino acid with 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. 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
0.071
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.52
CADD
Benign
1.4
DANN
Benign
0.53
DEOGEN2
Benign
0.056
T;.;.;.;.
Eigen
Benign
-0.96
Eigen_PC
Benign
-0.99
FATHMM_MKL
Benign
0.039
N
LIST_S2
Benign
0.41
T;T;.;T;.
M_CAP
Benign
0.018
T
MetaRNN
Benign
0.069
T;T;T;T;T
MetaSVM
Benign
-0.73
T
MutationAssessor
Benign
1.8
L;.;.;.;.
MutationTaster
Benign
1.0
N;N;N;N;N
PrimateAI
Benign
0.27
T
PROVEAN
Benign
-0.54
N;N;.;.;.
REVEL
Benign
0.11
Sift
Benign
0.57
T;T;.;.;.
Sift4G
Benign
0.58
T;T;.;.;.
Polyphen
0.34
B;B;.;.;B
Vest4
0.13
MutPred
0.17
Loss of loop (P = 0.0203);.;.;.;.;
MVP
0.53
MPC
0.036
ClinPred
0.12
T
GERP RS
1.3
Varity_R
0.025
gMVP
0.24

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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: rs1554297760; hg19: chr7-6026967; API