rs777286241

Positions:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000535.7(PMS2):c.779C>T(p.Ser260Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000829 in 1,591,390 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S260S) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000090 ( 3 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.588

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]

PMS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03243044).

BS2

High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7 linkuse as main transcript	c.779C>T	p.Ser260Phe	missense_variant	7/15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12 linkuse as main transcript	c.779C>T	p.Ser260Phe	missense_variant	7/15	1	NM_000535.7	ENSP00000265849	P3	P54278-1

Frequencies

GnomAD3 genomes

AF:

0.0000200

AC:

AN:

150328

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000666

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000418

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000199

AC:

AN:

250984

Hom.:

AF XY:

0.000287

AC XY:

AN XY:

135678

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00157

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000895

AC:

129

AN:

1441062

Hom.:

Cov.:

AF XY:

0.000131

AC XY:

AN XY:

718522

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00141

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000457

Gnomad4 OTH exome

AF:

0.0000335

GnomAD4 genome

AF:

0.0000200

AC:

AN:

150328

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73160

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000666

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000418

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.000272

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

PMS2-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2023

The PMS2 c.779C>T variant is predicted to result in the amino acid substitution p.Ser260Phe. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.16% of alleles in individuals of South Asian descent in gnomAD, including a homozygous individual (http://gnomad.broadinstitute.org/variant/7-6036981-G-A). This variant has been interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/827258/). Although we suspect that 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. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 15, 2019

The p.S260L variant (also known as c.779C>T), located in coding exon 7 of the PMS2 gene, results from a C to T substitution at nucleotide position 779. The serine at codon 260 is replaced by leucine, an amino acid with dissimilar 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. -

Lynch syndrome 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

The missense c.779C>T (p.Ser260Phe) variant in PMS2 gene has been submitted to ClinVar as a Variant of Uncertain Significance, but no details are available for independent assessment. It has not been reported in affected individuals. Thep.Ser260Phe variant is observed in 0.01% alleles in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The amino acid Ser at position 260 is changed to a Phe changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain significance. This variant has also been identified in an unaffected brother. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

T;.;.;.;.;.

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.71

T;T;.;T;.;T

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.032

T;T;T;T;T;T

MetaSVM

Benign

-0.49

MutationAssessor

Benign

1.2

L;.;.;.;.;L

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-3.3

D;D;.;.;.;N

REVEL

Uncertain

0.37

Sift

Uncertain

0.015

D;D;.;.;.;D

Sift4G

Benign

0.093

T;T;.;.;.;D

Polyphen

0.87

P;P;.;.;P;P

Vest4

0.28

MVP

0.84

MPC

0.040

ClinPred

0.069

GERP RS

0.13

Varity_R

0.22

gMVP

0.42

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over