rs188006077

Positions:

chr7-6003724-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP3_ModeratePP5

The NM_000535.7(PMS2):c.319C>T(p.Arg107Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000813 in 1,598,850 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). Synonymous variant affecting the same amino acid position (i.e. R107R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:1

Conservation

PhyloP100: 5.84

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.918

PP5

Variant 7-6003724-G-A is Pathogenic according to our data. Variant chr7-6003724-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127789.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Uncertain_significance=1, Pathogenic=1}. Variant chr7-6003724-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7 linkuse as main transcript	c.319C>T	p.Arg107Trp	missense_variant	4/15	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.319C>T	p.Arg107Trp	missense_variant	4/15	1	NM_000535.7	ENSP00000265849	P3	P54278-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

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:

0.0000127

AC:

AN:

236786

Hom.:

AF XY:

0.00

AC XY:

AN XY:

129932

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000553

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000183

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000829

AC:

AN:

1446654

Hom.:

Cov.:

AF XY:

0.00000416

AC XY:

AN XY:

720294

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000843

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 16, 2023	The frequency of this variant in the general population, 0.000013 (3/236786 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals and families affected with a Lynch syndrome associated cancer (PMIDs: 25512458 (2015), 27742654 (2017), 30702970 (2019)) and in an individual affected with CMMRD (PMID: 27435373 (2016)). Functional assays have shown this variant causes aberrant splicing and deficient mismatch repair activity (PMIDs: 26247049 (2015), 27435373 (2016)). Based on the available information, this variant is classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 12, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 27742654, 26110232, 25512458, 26247049, 27435373, 11574484, 30702970, 29445031, 31783044, 36690767, 32571878) -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 07, 2023	This missense variant replaces arginine with tryptophan at codon 107 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). Functional studies have shown that this variant causes a significant decrease in mismatch repair activity, with less than 20% of wild type protein activity (PMID: 27435373). This variant has been reported in individuals with Lynch syndrome-associated cancers (PMID: 27435373; ClinVar SCV000187425.8). This variant has also been observed in trans with a PMS2 exon 10 deletion in an individual affected with autosomal recessive constitutional mismatch repair deficiency (PMID: 27435373), indicating that this variant contributes to disease. This variant has been identified in 3/236786 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 24, 2023	The p.R107W variant (also known as c.319C>T), located in coding exon 4 of the PMS2 gene, results from a C to T substitution at nucleotide position 319. The arginine at codon 107 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been reported in trans with a PMS2 exon 10 deletion in a patient with suspected CMMRD; however, PMS2 protein expression was normal by immunohistochemistry (IHC) performed on the patient's tumor sample (van der Klift HM et al. Hum. Mutat. 2016 Nov;37:1162-1179). This alteration has also been identified in several individuals whose family history met Amsterdam II criteria for Lynch syndrome and/or colorectal tumors showed normal PMS2 protein expression on IHC, but displayed high microsatellite instability (MSI-H) (Ambry internal data; van der Klift HM et al. Hum. Mutat. 2016 11;37:1162-1179). In an in vitro mismatch repair (MMR) complementation assay, the MMR activity of p.R107W was reduced to less than 20% compared to wild type (100%), which was similar to other pathogenic/likely pathogenic variants in the assay (van der Klift HM et al. Hum. Mutat. 2016 11;37:1162-1179). Patient RNA analysis and in vitro minigene assays of the c.319C>T variant both demonstrated expression of alternatively spliced transcripts in addition to the full length PMS2 transcript, but this was not directly quantified (van der Klift HM et al. Mol. Genet. Genomic Med. 2015 Jul;3:327-45). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

PMS2-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 23, 2024

The PMS2 c.319C>T variant is predicted to result in the amino acid substitution p.Arg107Trp. This variant has been described as heterozygous in an individual with Lynch syndrome and in trans with a pathogenic variant in an individual with constitutional mismatch repair deficiency (CMMRD) syndrome (van der Klift et al. 2016. PubMed ID: 27435373). Additional individuals affected with Lynch syndrome associated cancer have also been reported with this variant (Supplementary Table 2, ten Broeke et al. 2015. PubMed ID: 25512458; Table 3, Salvador et al. 2019. PubMed ID: 30702970). Functional studies have demonstrated that this missense change affects PMS2 function wherein the mismatch repair activity was reduced to less than 20% compared to wild type (van der Klift et al. 2016. PubMed ID: 27435373). This variant is reported in 0.0055% of alleles in individuals of East Asian descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/127789/). This variant is interpreted as likely pathogenic. -

Hereditary nonpolyposis colorectal neoplasms

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 30, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 107 of the PMS2 protein (p.Arg107Trp). This variant is present in population databases (rs188006077, gnomAD 0.002%). This missense change has been observed in individual(s) with constitutional mismatch repair deficiency syndrome and Lynch syndrome (PMID: 25512458, 26110232, 27435373, 30702970). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 127789). 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: 27435373). Studies have shown that this missense change is associated with inconclusive levels of altered splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. -

Lynch syndrome 4

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 10, 2024

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 10, 2020

Variant summary: PMS2 c.319C>T (p.Arg107Trp) results in a non-conservative amino acid change located in the DNA mismatch repair protein family, N-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Although the c.319C>T falls within exon 4, and 4/4 programs in Alamut predict that this variant does not affect normal splicing, splicing studies have shown that this variant promotes the expression of the alternative transcripts lacking exon 4 over full-length (FL) transcripts (van der Klift_2015). The alternative transcripts are also found in wt RNA, and, since the exact differences in the rate of expression of the FL and alternative transcripts could not be determined, the translational impact of this variant remains uncertain. The variant allele was found at a frequency of 1.3e-05 in 236786 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.319C>T has been reported in the literature in individuals affected with or with a family history of Lynch Syndrome-spectrum cancers, as well as in at least one patient with suspected CMMRD who carried a second pathogenic variant (van der Klift_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. In one patient with endometrial cancer, co-occurrence with another pathogenic variant was reported (POLE, p.R563*), providing supporting evidence for a benign role (Stelloo_2017). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, four classified as VUS while one classified as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.82

D;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Uncertain

0.29

MetaRNN

Pathogenic

0.92

D;D

MetaSVM

Pathogenic

0.88

MutationAssessor

Pathogenic

4.8

H;H

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-7.0

D;D

REVEL

Pathogenic

0.76

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

1.0

MVP

0.97

MPC

0.28

ClinPred

1.0

GERP RS

5.7

Varity_R

0.99

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.29

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.29

Position offset: -34

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