7-5997396-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_000535.7(PMS2):c.733C>A(p.Leu245Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000313 in 1,598,210 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L245V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000068 ( 0 hom., cov: 28)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.11

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 3 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 17 uncertain in NM_000535.7

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28424627).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7 linkuse as main transcript	c.733C>A	p.Leu245Met	missense_variant	7/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12 linkuse as main transcript	c.733C>A	p.Leu245Met	missense_variant	7/15	1	NM_000535.7	P3	P54278-1

Frequencies

GnomAD3 genomes

AF:

0.00000676

AC:

AN:

147940

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000290

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:

0.00000406

AC:

AN:

246016

Hom.:

AF XY:

0.00000752

AC XY:

AN XY:

132906

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000276

AC:

AN:

1450270

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

722082

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.00000676

AC:

AN:

147940

Hom.:

Cov.:

AF XY:

0.0000140

AC XY:

AN XY:

71576

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000290

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

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2016	This variant is denoted PMS2 c.733C>A at the cDNA level, p.Leu245Met (L245M) at the protein level, and results in the change of a Leucine to a Methionine (CTG>ATG). This variant was observed in 1/572 individuals with atherosclerosis, with no specific information about cancer history (Johnston 2012). PMS2 Leu245Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Leucine and Methionine share similar properties, this is considered a conservative amino acid substitution. PMS2 Leu245Met occurs at a position that is not conserved and is located within the ATPase domain (Fukui 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether PMS2 Leu245Met is pathogenic or benign. We consider it to be a variant of uncertain significance. -
Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 14, 2022	The c.733C>A (p.L245M) alteration is located in exon 7 (coding exon 7) of the PMS2 gene. This alteration results from a C to A substitution at nucleotide position 733, causing the leucine (L) at amino acid position 245 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 11, 2020	This missense variant replaces leucine with methionine at codon 245 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/246016 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hereditary nonpolyposis colorectal neoplasms

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 11, 2024

This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 245 of the PMS2 protein (p.Leu245Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 41719). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PMS2 protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Uncertain

0.065

BayesDel_noAF

Benign

-0.14

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.12

T;.;.;.;.;.

Eigen

Benign

0.17

Eigen_PC

Benign

0.21

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.70

T;T;.;T;.;T

M_CAP

Benign

0.030

MetaRNN

Benign

0.28

T;T;T;T;T;T

MetaSVM

Uncertain

0.53

MutationAssessor

Pathogenic

2.9

M;.;.;.;.;M

MutationTaster

Benign

0.95

D;D;D;D;N

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.93

N;N;.;.;.;N

REVEL

Uncertain

0.36

Sift

Uncertain

0.022

D;D;.;.;.;T

Sift4G

Benign

0.067

T;T;.;.;.;T

Polyphen

0.89

P;D;.;.;D;P

Vest4

0.43

MutPred

0.37

Loss of helix (P = 0.0558);.;.;.;.;Loss of helix (P = 0.0558);

MVP

0.85

MPC

0.22

ClinPred

0.82

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.32

gMVP

0.24

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