rs376042544

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_000535.7(PMS2):​c.1279C>T​(p.Arg427Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R427H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

2
6
11

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:2

Conservation

PhyloP100: 4.03
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 Likely_benign. Variant got -3 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.14388698).
BP6
Variant 7-5987486-G-A is Benign according to our data. Variant chr7-5987486-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127758.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=6}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PMS2NM_000535.7 linkuse as main transcriptc.1279C>T p.Arg427Cys missense_variant 11/15 ENST00000265849.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PMS2ENST00000265849.12 linkuse as main transcriptc.1279C>T p.Arg427Cys missense_variant 11/151 NM_000535.7 P3P54278-1

Frequencies

GnomAD3 genomes
AF:
0.000105
AC:
16
AN:
152154
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000362
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000279
AC:
7
AN:
250898
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135688
show subpopulations
Gnomad AFR exome
AF:
0.000370
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000123
AC:
18
AN:
1461822
Hom.:
0
Cov.:
34
AF XY:
0.00000825
AC XY:
6
AN XY:
727208
show subpopulations
Gnomad4 AFR exome
AF:
0.000388
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.000105
AC:
16
AN:
152154
Hom.:
0
Cov.:
31
AF XY:
0.000108
AC XY:
8
AN XY:
74314
show subpopulations
Gnomad4 AFR
AF:
0.000362
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.000121
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000412
AC:
5

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:6Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoDec 06, 2022The frequency of this variant in the general population, 0.00048 (12/24942 chromosomes in African/African American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been briefly reported in a study of prostate cancer (PMID: 32832836 (2020)) as well as in an MMR proficient endometrial tumor that had other clinically significant variants (PMID: 35002543 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMay 01, 2020- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxOct 26, 2023In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25808843, 35002543) -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthOct 22, 2020- -
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 10, 2022The p.R427C variant (also known as c.1279C>T), located in coding exon 11 of the PMS2 gene, results from a C to T substitution at nucleotide position 1279. The arginine at codon 427 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is poorly 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. -
PMS2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesNov 04, 2022The PMS2 c.1279C>T variant is predicted to result in the amino acid substitution p.Arg427Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.048% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-6027117-G-A) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127758/). Although we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Lynch syndrome 4 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsMar 28, 2024- -
Hereditary nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitterclinical testingInvitaeJan 28, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.079
BayesDel_addAF
Benign
-0.26
T
BayesDel_noAF
Benign
-0.24
CADD
Uncertain
24
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.20
T;.;.;.;.
Eigen
Uncertain
0.32
Eigen_PC
Uncertain
0.35
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.94
D;D;.;D;.
M_CAP
Benign
0.055
D
MetaRNN
Benign
0.14
T;T;T;T;T
MetaSVM
Uncertain
0.23
D
MutationAssessor
Benign
1.4
L;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Benign
0.20
T
PROVEAN
Uncertain
-2.5
D;D;.;.;.
REVEL
Benign
0.23
Sift
Uncertain
0.0040
D;D;.;.;.
Sift4G
Benign
0.085
T;T;.;.;.
Polyphen
0.98
D;D;.;.;D
Vest4
0.35
MVP
0.68
MPC
0.12
ClinPred
0.24
T
GERP RS
5.8
Varity_R
0.065
gMVP
0.41

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.11
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: rs376042544; hg19: chr7-6027117; COSMIC: COSV99764665; API