7-5987144-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000535.7(PMS2):c.1621A>G(p.Lys541Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.85 in 1,611,014 control chromosomes in the GnomAD database, including 584,176 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K541R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.87 ( 57167 hom., cov: 32)

Exomes 𝑓: 0.85 ( 527009 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16O:1

Conservation

PhyloP100: 1.50

Publications

105 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.4039015E-6).

BP6

Variant 7-5987144-T-C is Benign according to our data. Variant chr7-5987144-T-C is described in ClinVar as Benign. ClinVar VariationId is 135065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.917 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7 link	c.1621A>G	p.Lys541Glu	missense_variant	Exon 11 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.1621A>G	p.Lys541Glu	missense_variant	Exon 11 of 15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes

AF:

0.865

AC:

131537

AN:

151998

Hom.:

57124

Cov.:

show subpopulations

Gnomad AFR

AF:

0.925

Gnomad AMI

AF:

0.938

Gnomad AMR

AF:

0.772

Gnomad ASJ

AF:

0.893

Gnomad EAS

AF:

0.915

Gnomad SAS

AF:

0.895

Gnomad FIN

AF:

0.843

Gnomad MID

AF:

0.899

Gnomad NFE

AF:

0.845

Gnomad OTH

AF:

0.855

GnomAD2 exomes

AF:

0.841

AC:

210907

AN:

250846

AF XY:

0.848

show subpopulations

Gnomad AFR exome

AF:

0.925

Gnomad AMR exome

AF:

0.669

Gnomad ASJ exome

AF:

0.889

Gnomad EAS exome

AF:

0.921

Gnomad FIN exome

AF:

0.839

Gnomad NFE exome

AF:

0.850

Gnomad OTH exome

AF:

0.840

GnomAD4 exome

AF:

0.849

AC:

1238139

AN:

1458898

Hom.:

527009

Cov.:

AF XY:

0.851

AC XY:

617868

AN XY:

725902

show subpopulations

African (AFR)

AF:

0.930

AC:

31094

AN:

33450

American (AMR)

AF:

0.681

AC:

30438

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.887

AC:

23166

AN:

26120

East Asian (EAS)

AF:

0.930

AC:

36932

AN:

39692

South Asian (SAS)

AF:

0.893

AC:

77017

AN:

86218

European-Finnish (FIN)

AF:

0.842

AC:

44914

AN:

53336

Middle Eastern (MID)

AF:

0.868

AC:

4999

AN:

5762

European-Non Finnish (NFE)

AF:

0.845

AC:

937635

AN:

1109296

Other (OTH)

AF:

0.861

AC:

51944

AN:

60306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.413

Heterozygous variant carriers

7638

15277

22915

30554

38192

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21040

42080

63120

84160

105200

<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:

0.865

AC:

131629

AN:

152116

Hom.:

57167

Cov.:

AF XY:

0.864

AC XY:

64262

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.925

AC:

38418

AN:

41530

American (AMR)

AF:

0.771

AC:

11747

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.893

AC:

3098

AN:

3470

East Asian (EAS)

AF:

0.914

AC:

4730

AN:

5174

South Asian (SAS)

AF:

0.895

AC:

4318

AN:

4826

European-Finnish (FIN)

AF:

0.843

AC:

8912

AN:

10572

Middle Eastern (MID)

AF:

0.895

AC:

263

AN:

294

European-Non Finnish (NFE)

AF:

0.845

AC:

57482

AN:

67996

Other (OTH)

AF:

0.857

AC:

1807

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

896

1792

2687

3583

4479

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

894

1788

2682

3576

4470

<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:

0.854

Hom.:

101673

Bravo

AF:

0.859

TwinsUK

AF:

0.847

AC:

3141

ALSPAC

AF:

0.834

AC:

3216

ESP6500AA

AF:

0.918

AC:

4045

ESP6500EA

AF:

0.846

AC:

7270

ExAC

AF:

0.851

AC:

103334

Asia WGS

AF:

0.891

AC:

3101

AN:

3478

EpiCase

AF:

0.851

EpiControl

AF:

0.850

ClinVar

Significance: Benign

Submissions summary: Benign:16Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9Other:1

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Feb 05, 2018

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Oct 11, 2016

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Disclaimer: This variant has not undergone full assessment. The following are pr eliminary notes: Frequency

Lynch syndrome 4

Benign:3

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 18, 2017

IntelligeneCG

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Lynch syndrome

Benign:2

Oct 03, 2024

All of Us Research Program, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 10, 2025

GeneKor MSA

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mismatch repair cancer syndrome 4

Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.50

CADD

Benign

5.5

(source)

DANN

Benign

0.22

DEOGEN2

Benign

0.052

T;.;.;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.00058

LIST_S2

Benign

0.22

T;T;.;T;.

MetaRNN

Benign

0.0000014

T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-1.9

N;.;.;.;.

PhyloP100

1.5

PrimateAI

Benign

0.25

PROVEAN

Benign

0.76

N;N;.;.;.

REVEL

Benign

0.16

Sift

Benign

1.0

T;T;.;.;.

Sift4G

Benign

1.0

T;T;.;.;.

Vest4

0.049

ClinPred

0.0016

GERP RS

4.7

Varity_R

0.044

gMVP

0.15

Mutation Taster

=97/3

polymorphism (auto)

(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