rs375968016

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_000535.7(PMS2):c.2437C>T(p.Arg813Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000613 in 1,565,522 control chromosomes in the GnomAD database, including 1 homozygotes. 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. R813L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000052 ( 1 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:13B:2

Conservation

PhyloP100: 5.11

Publications

11 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: Uncertain_significance. The variant received 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.815

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7 link	c.2437C>T	p.Arg813Trp	missense_variant	Exon 14 of 15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12 link	c.2437C>T	p.Arg813Trp	missense_variant	Exon 14 of 15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes

AF:

0.000148

AC:

AN:

148678

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000468

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000200

Gnomad SAS

AF:

0.000215

Gnomad FIN

AF:

0.0000993

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000107

AC:

AN:

206338

AF XY:

0.0000798

show subpopulations

Gnomad AFR exome

AF:

0.000238

Gnomad AMR exome

AF:

0.0000325

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000381

Gnomad FIN exome

AF:

0.000107

Gnomad NFE exome

AF:

0.0000116

Gnomad OTH exome

AF:

0.000568

GnomAD4 exome

AF:

0.0000522

AC:

AN:

1416744

Hom.:

Cov.:

AF XY:

0.0000439

AC XY:

AN XY:

705676

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000458

AC:

AN:

32770

American (AMR)

AF:

0.0000227

AC:

AN:

44090

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25858

East Asian (EAS)

AF:

0.000231

AC:

AN:

39008

South Asian (SAS)

AF:

0.000225

AC:

AN:

84588

European-Finnish (FIN)

AF:

0.0000381

AC:

AN:

52452

Middle Eastern (MID)

AF:

0.000181

AC:

AN:

5538

European-Non Finnish (NFE)

AF:

0.0000196

AC:

AN:

1073592

Other (OTH)

AF:

0.000102

AC:

AN:

58848

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.365

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:

0.000148

AC:

AN:

148778

Hom.:

Cov.:

AF XY:

0.000138

AC XY:

AN XY:

72394

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000467

AC:

AN:

40706

American (AMR)

AF:

0.00

AC:

AN:

14904

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3428

East Asian (EAS)

AF:

0.000201

AC:

AN:

4976

South Asian (SAS)

AF:

0.000215

AC:

AN:

4658

European-Finnish (FIN)

AF:

0.0000993

AC:

AN:

10070

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66786

Other (OTH)

AF:

0.00

AC:

AN:

2048

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.316

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:

0.00

Hom.:

ESP6500AA

AF:

0.000867

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000673

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:13Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Mar 21, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

May 22, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In the published literature, the variant has been reported in individuals with a personal or family history of colorectal cancer (PMID: 26900293 (2016), 33413596 (2021)) and breast cancer (PMID: 35449176 (2022), 36200007 (2022)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in unaffected individuals (see LOVD (http://databases.lovd.nl/shared/genes/PMS2) and PMID: 33471991 (2021)). The frequency of this variant in the general population, 0.00035 (6/17216 chromosomes in East Asian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

Jul 15, 2024

GeneDx

Significance:Uncertain significance

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 individual(s) with breast cancer (PMID: 36200007); This variant is associated with the following publications: (PMID: 26900293, 33413596, 37534630, 18619468, 36200007)

Hereditary cancer-predisposing syndrome

Uncertain:3

Nov 03, 2022

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 813 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 colorectal cancer (PMID: 26900293, 34172528). This variant has been identified in 19/201724 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.

Jan 23, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R813W variant (also known as c.2437C>T), located in coding exon 14 of the PMS2 gene, results from a C to T substitution at nucleotide position 2437. The arginine at codon 813 is replaced by tryptophan, an amino acid with dissimilar properties. One study detected this alteration in 1/103 individuals diagnosed with colorectal cancer (Chang YC et al. World J. Gastroenterol., 2016 Feb;22:2314-25). This alteration has also been reported in a cohort of 235 individuals diagnosed with breast cancer (Mittal A et al. Ecancermedicalscience, 2022 Aug;16:1434). 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 available evidence, the clinical significance of this variant remains unclear.

Apr 13, 2025

Hereditary Cancer Laboratory, Hospital Universitario 12 de Octubre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2Supporting+PP3Moderate

not specified

Uncertain:2

Jan 13, 2025

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PMS2 c.2437C>T (p.Arg813Trp) 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 6.1e-05 in 1565522 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer (6.1e-05 vs 7.1e-05), allowing no conclusion about variant significance. Additionally, this allele frequency needs to be cautiously considered due to the possibility of the PMS2 pseudogene being captured. c.2437C>T has been reported in the literature in individuals affected with Colorectal Cancer (Chang_2016), therapy-related myeloid neoplasms (Singhal_2021), gastric cancer (Zhang_2021), and breast cancer (Hu_2022, Mittal_2022), or with suspected unspecified cancer syndrome (Bouras_2024), however, all without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 37534630, 33413596, 26900293, 35449176, 36200007, 33850299, 34567566). ClinVar contains an entry for this variant (Variation ID: 127783). Based on the evidence outlined above, the variant was classified as uncertain significance.

Oct 21, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Lynch syndrome 4

Uncertain:2

Mar 08, 2025

Molecular Pathology, Peter Maccallum Cancer Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 18, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Uncertain:1

Sep 19, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

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:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary cancer

Benign:1

Jan 23, 2024

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.51

D;.;.;.;.;.

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.75

LIST_S2

Pathogenic

1.0

D;D;.;D;.;D

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.82

D;D;D;D;D;D

MetaSVM

Uncertain

0.61

MutationAssessor

Pathogenic

3.8

H;.;.;.;.;.

PhyloP100

5.1

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-7.0

D;D;.;.;.;D

Sift

Pathogenic

0.0

D;D;.;.;.;D

Sift4G

Pathogenic

0.0

D;D;.;.;.;D

Vest4

0.99

ClinPred

0.97

GERP RS

4.8

Varity_R

0.95

gMVP

0.91

Mutation Taster

=8/92

disease causing

(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