7-6002484-C-T

Position:

chr7-6002484-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM5PP3_Moderate

The NM_000535.7(PMS2):c.506G>A(p.Arg169His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,611,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R169C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:9

Conservation

PhyloP100: 7.50

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 4 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-6002485-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1745085.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.906

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7 linkuse as main transcript	c.506G>A	p.Arg169His	missense_variant	5/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12 linkuse as main transcript	c.506G>A	p.Arg169His	missense_variant	5/15	1	NM_000535.7	P3	P54278-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000801

AC:

AN:

249642

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135184

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1458960

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

725826

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000307

Hom.:

Bravo

AF:

0.0000113

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Lynch syndrome 4

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 02, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 19, 2023	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 35451539]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Lynch syndrome

Uncertain:2

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.506G>A has a 60.9% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 28, 2023	This missense variant replaces arginine with histidine at codon 169 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study analyzing somatic driver variants was inconclusive for this variant (PMID: 29887214). have not been reported for this variant. This variant has been reported in an individual affected with Lynch syndrome (PMID: 31433215) and an individual affected with breast cancer (PMID: 30039884). This variant has been identified in 3/281050 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 cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 15, 2023	The p.R169H variant (also known as c.506G>A), located in coding exon 5 of the PMS2 gene, results from a G to A substitution at nucleotide position 506. The arginine at codon 169 is replaced by histidine, an amino acid with highly similar properties. Using a Bayesian analysis that incorporates tumor mutation data, this variant was classified as a variant of uncertain significance (Shirts BH et al. Am J Hum Genet. 2018 Jul 5;103(1):19-29). In an in vitro complementation assay, this variant had reduced mismatch repair activity compared to wild type PMS2 (Rayner E et al. Hum Mutat, 2022 Sep;43:1249-1258). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 17, 2023	This missense variant replaces arginine with histidine at codon 169 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Lynch syndrome (PMID: 31433215) and an individual affected with breast cancer (PMID: 30039884). This variant has been identified in 3/281050 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. -

PMS2-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 22, 2023

The PMS2 c.506G>A variant is predicted to result in the amino acid substitution p.Arg169His. This variant has been reported in a patient with Lynch syndrome (Okkels et al. 2019. PubMed ID: 31433215), an individual with breast cancer (Dong et al. 2018. PubMed ID: 30039884), and in a study of somatic mutations in tumors (Table S3, Shirts et al. 2018. PubMed ID: 29887214). This variant is reported in 0.0023% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-6042115-C-T) and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/182811/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Lynch syndrome 4;C5399763:Mismatch repair cancer syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 27, 2017

This variant is denoted PMS2 c.506G>A at the cDNA level, p.Arg169His (R169H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Arg169His was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. PMS2 Arg169His occurs at a position that is conserved across species 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 Arg169His 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

Invitae

Jan 15, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 169 of the PMS2 protein (p.Arg169His). This variant is present in population databases (rs730881917, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer and clinical features of Lynch syndrome (PMID: 30039884, 31433215). ClinVar contains an entry for this variant (Variation ID: 182811). 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 expected to disrupt PMS2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PMS2 function (PMID: 35451539). 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

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.74

D;.;.;.;.;.

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.83

T;D;.;D;.;D

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.91

D;D;D;D;D;D

MetaSVM

Uncertain

0.64

MutationAssessor

Pathogenic

3.9

H;.;.;.;.;H

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-4.4

D;D;.;.;.;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D;.;.;.;D

Sift4G

Pathogenic

0.0

D;D;.;.;.;D

Polyphen

1.0

D;D;.;.;D;P

Vest4

0.99

MVP

0.99

MPC

0.28

ClinPred

1.0

GERP RS

5.4

Varity_R

0.86

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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