rs867655834

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1

The ENST00000265849.12(PMS2):c.727G>T(p.Val243Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V243L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 28)

Exomes 𝑓: 0.000091 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PMS2
ENST00000265849.12 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 2.98

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 Uncertain_significance. Variant got 2 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 16 uncertain in ENST00000265849.12

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7 linkuse as main transcript	c.727G>T	p.Val243Phe	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.727G>T	p.Val243Phe	missense_variant	7/15	1	NM_000535.7	ENSP00000265849	P3	P54278-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

121238

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.000284

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000903

Gnomad ASJ

AF:

0.000323

Gnomad EAS

AF:

0.000227

Gnomad SAS

AF:

0.000537

Gnomad FIN

AF:

0.000154

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000172

Gnomad OTH

AF:

0.000611

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000910

AC:

127

AN:

1395922

Hom.:

Cov.:

AF XY:

0.0000961

AC XY:

AN XY:

696938

show subpopulations

Gnomad4 AFR exome

AF:

0.0000953

Gnomad4 AMR exome

AF:

0.000193

Gnomad4 ASJ exome

AF:

0.000118

Gnomad4 EAS exome

AF:

0.000153

Gnomad4 SAS exome

AF:

0.000219

Gnomad4 FIN exome

AF:

0.0000379

Gnomad4 NFE exome

AF:

0.0000774

Gnomad4 OTH exome

AF:

0.0000861

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000214

AC:

AN:

121302

Hom.:

Cov.:

AF XY:

0.000224

AC XY:

AN XY:

57950

show subpopulations

Gnomad4 AFR

AF:

0.000283

Gnomad4 AMR

AF:

0.0000902

Gnomad4 ASJ

AF:

0.000323

Gnomad4 EAS

AF:

0.000227

Gnomad4 SAS

AF:

0.000540

Gnomad4 FIN

AF:

0.000154

Gnomad4 NFE

AF:

0.000172

Gnomad4 OTH

AF:

0.000606

Alfa

AF:

0.0000882

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 09, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 12, 2017	The p.V243F variant (also known as c.727G>T), located in coding exon 7 of the PMS2 gene, results from a G to T substitution at nucleotide position 727. The valine at codon 243 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Lynch syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

University of Washington Department of Laboratory Medicine, University of Washington

May 01, 2018

PMS2 NM_000535.5:c.727G>T has a 16.7% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.20 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the PMS2 locus. See Shirts et al 2018, PMID 29887214. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 15, 2016

This variant is denoted PMS2 c.727G>T at the cDNA level, p.Val243Phe (V243F) at the protein level, and results in the change of a Valine to a Phenylalanine (GTT>TTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Val243Phe was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Valine and Phenylalanine differ in some properties, this is considered a semi-conservative amino acid substitution. PMS2 Val243Phe occurs at a position that is conserved in mammals and is located in the ATPase domain (Guarne 2001). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether PMS2 Val243Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Hereditary nonpolyposis colorectal neoplasms

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 21, 2021

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 419274). This missense change has been observed in individual(s) with breast cancer (PMID: 29752822). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with phenylalanine at codon 243 of the PMS2 protein (p.Val243Phe). The valine residue is moderately conserved and there is a small physicochemical difference between valine and phenylalanine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

T;.;.;.;.;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.94

D;D;.;D;.;D

M_CAP

Benign

0.052

MetaRNN

Uncertain

0.42

T;T;T;T;T;T

MetaSVM

Uncertain

0.56

MutationAssessor

Uncertain

2.9

M;.;.;.;.;M

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.7

D;N;.;.;.;N

REVEL

Uncertain

0.58

Sift

Benign

0.063

T;T;.;.;.;T

Sift4G

Uncertain

0.050

T;T;.;.;.;T

Polyphen

0.81

P;D;.;.;D;D

Vest4

0.66

MutPred

0.51

Loss of helix (P = 0.1299);.;.;.;.;Loss of helix (P = 0.1299);

MVP

0.92

MPC

0.18

ClinPred

0.40

GERP RS

5.4

Varity_R

0.48

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.23

Position offset: -6

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