rs149202766

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 1P and 11B. PP3BP4_ModerateBP6BS1BS2

The NM_000535.7(PMS2):c.2395C>T(p.Arg799Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000252 in 1,598,362 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign 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. R799Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0014 ( 9 hom., cov: 30)

Exomes 𝑓: 0.00013 ( 3 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4B:9

Conservation

PhyloP100: 2.73

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

Lynch syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Lynch syndrome 4
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
mismatch repair cancer syndrome 1
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
mismatch repair cancer syndrome 4
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
malignant pancreatic neoplasm
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
ovarian cancer
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
Muir-Torre syndrome
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
rhabdomyosarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
breast cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
prostate cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

PMS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 11: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, MutationAssessor, PrimateAI, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, phyloP100way_vertebrate was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.07591587).

BP6

Variant 7-5977638-G-A is Benign according to our data. Variant chr7-5977638-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 91340.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0014 (209/149640) while in subpopulation AMR AF = 0.0118 (177/15002). AF 95% confidence interval is 0.0104. There are 9 homozygotes in GnomAd4. There are 141 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7 link	c.2395C>T	p.Arg799Trp	missense_variant	Exon 14 of 15	ENST00000265849.12	NP_000526.2	P54278-1Q7Z3Q2B4DGM0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12 link	c.2395C>T	p.Arg799Trp	missense_variant	Exon 14 of 15	1	NM_000535.7	ENSP00000265849.7		P54278-1

Frequencies

GnomAD3 genomes

AF:

0.00139

AC:

208

AN:

149538

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000540

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000119

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000512

AC:

122

AN:

238072

AF XY:

0.000387

show subpopulations

Gnomad AFR exome

AF:

0.000661

Gnomad AMR exome

AF:

0.00309

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000380

Gnomad OTH exome

AF:

0.000342

GnomAD4 exome

AF:

0.000134

AC:

194

AN:

1448722

Hom.:

Cov.:

AF XY:

0.000133

AC XY:

AN XY:

720896

show subpopulations

African (AFR)

AF:

0.000482

AC:

AN:

33188

American (AMR)

AF:

0.00309

AC:

138

AN:

44592

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26068

East Asian (EAS)

AF:

0.00

AC:

AN:

39346

South Asian (SAS)

AF:

0.0000234

AC:

AN:

85566

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52910

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.0000281

AC:

AN:

1101414

Other (OTH)

AF:

0.000117

AC:

AN:

59906

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.409

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00140

AC:

209

AN:

149640

Hom.:

Cov.:

AF XY:

0.00193

AC XY:

141

AN XY:

72880

show subpopulations

African (AFR)

AF:

0.000563

AC:

AN:

40858

American (AMR)

AF:

0.0118

AC:

177

AN:

15002

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3444

East Asian (EAS)

AF:

0.00

AC:

AN:

5028

South Asian (SAS)

AF:

0.00

AC:

AN:

4682

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10208

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000119

AC:

AN:

67150

Other (OTH)

AF:

0.00

AC:

AN:

2066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000422

Hom.:

Bravo

AF:

0.00123

ESP6500AA

AF:

0.00142

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.000158

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:4Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:2

Jan 09, 2025

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PMS2 c.2395C>T (p.Arg799Trp) results in a non-conservative amino acid change located in the MutL, C-terminal, dimerisation domain (IPR014790) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 1598362 control chromosomes, predominantly at a frequency of 0.0053 within the Latino subpopulation in the gnomAD database, including 11 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database (v4) is approximately 75 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (7.1e-05). This observation needs to be cautiously considered due to the possibility of the PMS2 pseudogene being captured, although the observation of at least 11 homozygotes, decreases the likelihood of a pseudogene artefact. c.2395C>T has been reported in the literature in sequencing studies of individuals affected with pancreatic cancer, Lynch Syndrome and hereditary breast and ovarian cancer syndrome (e.g. Cock-Rada_2017, Hu_2016, Li_2020, Oliver_2019, Sunga_2017, Yurgelun_2017, Zahary_2014). Specifically, Zahary_2014 reports the variant in one suspected Lynch syndrome patient who was indicated to have absent PMS2 protein expression, although the IHC findings from MLH1 and MSH2 were not provided. Furthermore, co-occurrence and cosegregation data and MLH1 gene testing results were not reported. These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. At-least one co-occurrence with another pathogenic variant has been reported in a HBOC patient (BRCA1 c.1674delA, p.Gly559fsX13; Cock-Rada_2017), providing additional supporting evidence for a non-pathogenic role attributed to this variant. The following publications have been ascertained in the context of this evaluation (PMID: 26483394, 26333163, 24072394, 28135145, 28528518, 28449805, 30122538, 31391288, 31921681, 35449176). ClinVar contains an entry for this variant (Variation ID: 91340). Based on the evidence outlined above, the variant was classified as likely benign. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 20, 2021

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNA sequence analysis of the PMS2 gene demonstrated a sequence change, c.2395C>T, in exon 14 that results in an amino acid change, p.Arg799Trp. This sequence change has been described in the gnomAD database with a frequency of 0.31% in the Latino/Admixed American subpopulation including one homozygous individual (dbSNP rs149202766). The p.Arg799Trp change affects a highly conserved amino acid residue located in a domain of the PMS2 protein that is known to be functional. The p.Arg799Trp substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been identified in individuals evaluated for Lynch syndrome, in an individual with pancreatic adenocarcinoma, and in individuals assessed for hereditary breast and ovarian cancer (PMID: 28449805, 28528518, 24072394, 2648339). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg799Trp change remains unknown at this time. -

not provided

Uncertain:1Benign:1

Jun 02, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history of Lynch syndrome-related cancers, at least one of whom had tumor studies consistent with pathogenic variants in this gene (Zahary 2014, Hu 2016, Sunga 2017, Yurgelun 2017, Cock-Rada 2018, Oliver 2019, Li 2020); This variant is associated with the following publications: (PMID: 24072394, 26483394, 26798439, 28135145, 26333163, 28528518, 30979843, 30122538, 31391288, 31921681, 28449805) -

Apr 13, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The PMS2 c.2395C>T (p.Arg799Trp) variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMID: 35449176 (2022), 33471991 (2021), https://databases.lovd.nl/shared/variants/PMS2, 31921681 (2019), 28528518 (2017)), colorectal cancer (PMID: 28135145 (2017), 28449805 (2017), 24072394 (2014)), and pancreatic cancer (PMID: 26483394 (2015)). This variant has also been reported in reportedly healthy individuals in a large breast cancer association study (PMIDs: 33471991 (2021), https://databases.lovd.nl/shared/variants/PMS2). The frequency of this variant in the general population, 0.0031 (108/34802 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Dec 13, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Feb 19, 2025

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with tryptophan at codon 799 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 individuals affected with Lynch syndrome or Lynch syndrome-associated cancers (PMID: 24072394, 28135145, 28449805), breast/ovarian cancer (PMID: 28528518, 31921681 33471991), or pancreatic cancer (PMID: 26483394). This variant has been identified in 403/1598362 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in multiple healthy control individuals (PMID: 33471991). This observed population allele frequency is not considered reliable since the gnomAD dataset does not disambiguate possible interference from homologous sequences in the PMS2CL pseudogene. 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. -

Ovarian cancer

Pathogenic:1

Jan 01, 2022

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Significance:Likely pathogenic

Review Status:flagged submission

Collection Method:clinical testing

- -

Lynch syndrome 4;C5399763:Mismatch repair cancer syndrome 1

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PMS2-related disorder

Benign:1

May 16, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Lynch syndrome

Benign:1

Jul 29, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer

Benign:1

Feb 27, 2025

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity. -

Lynch syndrome 4

Benign:1

Feb 04, 2025

Myriad Genetics, Inc.

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.42

T;.;.;.;.;.

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.89

LIST_S2

Pathogenic

0.98

D;D;.;D;.;D

M_CAP

Pathogenic

0.45

MetaRNN

Benign

0.076

T;T;T;T;T;T

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

3.6

H;.;.;.;.;.

PhyloP100

2.7

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-6.7

D;D;.;.;.;D

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;D;.;.;.;D

Sift4G

Pathogenic

0.0

D;D;.;.;.;D

Polyphen

1.0

D;D;.;.;D;D

Vest4

0.94

MVP

0.97

MPC

3.3

ClinPred

0.16

GERP RS

3.7

Varity_R

0.88

gMVP

0.89

Mutation Taster

=81/19

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over