7-6005996-C-T

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.59G>A(p.Arg20Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.069 in 1,610,336 control chromosomes in the GnomAD database, including 4,147 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R20G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.074 ( 450 hom., cov: 32)

Exomes 𝑓: 0.068 ( 3697 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:24O:1

Conservation

PhyloP100: 0.288

Publications

57 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: Orphanet, ClinGen
Lynch syndrome 4
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
mismatch repair cancer syndrome 1
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
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=0.0026167035).

BP6

Variant 7-6005996-C-T is Benign according to our data. Variant chr7-6005996-C-T is described in ClinVar as Benign. ClinVar VariationId is 41716.Status of the report is reviewed_by_expert_panel, 3 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0887 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000535.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PMS2	NM_000535.7	MANE Select	c.59G>A	p.Arg20Gln	missense	Exon 2 of 15	NP_000526.2	P54278-1
PMS2	NM_001406866.1		c.245G>A	p.Arg82Gln	missense	Exon 3 of 16	NP_001393795.1	A0A8V8TNX6
PMS2	NM_001322014.2		c.59G>A	p.Arg20Gln	missense	Exon 2 of 15	NP_001308943.1	A0A8V8TQ50

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PMS2	ENST00000265849.12	TSL:1 MANE Select	c.59G>A	p.Arg20Gln	missense	Exon 2 of 15	ENSP00000265849.7	P54278-1
PMS2	ENST00000382321.5	TSL:1	c.59G>A	p.Arg20Gln	missense	Exon 2 of 11	ENSP00000371758.4	P54278-2
PMS2	ENST00000406569.8	TSL:1	n.59G>A		non_coding_transcript_exon	Exon 2 of 13	ENSP00000514464.1	P54278-3

Frequencies

GnomAD3 genomes

AF:

0.0744

AC:

11312

AN:

152042

Hom.:

448

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0899

Gnomad AMI

AF:

0.0417

Gnomad AMR

AF:

0.0491

Gnomad ASJ

AF:

0.0415

Gnomad EAS

AF:

0.0956

Gnomad SAS

AF:

0.0899

Gnomad FIN

AF:

0.0871

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0681

Gnomad OTH

AF:

0.0786

GnomAD2 exomes

AF:

0.0716

AC:

17574

AN:

245616

AF XY:

0.0727

show subpopulations

Gnomad AFR exome

AF:

0.0904

Gnomad AMR exome

AF:

0.0255

Gnomad ASJ exome

AF:

0.0418

Gnomad EAS exome

AF:

0.0954

Gnomad FIN exome

AF:

0.0832

Gnomad NFE exome

AF:

0.0756

Gnomad OTH exome

AF:

0.0646

GnomAD4 exome

AF:

0.0684

AC:

99812

AN:

1458176

Hom.:

3697

Cov.:

AF XY:

0.0692

AC XY:

50206

AN XY:

725440

show subpopulations

African (AFR)

AF:

0.0887

AC:

2962

AN:

33400

American (AMR)

AF:

0.0272

AC:

1216

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0391

AC:

1022

AN:

26124

East Asian (EAS)

AF:

0.0907

AC:

3598

AN:

39684

South Asian (SAS)

AF:

0.0886

AC:

7638

AN:

86160

European-Finnish (FIN)

AF:

0.0895

AC:

4681

AN:

52276

Middle Eastern (MID)

AF:

0.0537

AC:

222

AN:

4136

European-Non Finnish (NFE)

AF:

0.0668

AC:

74263

AN:

1111498

Other (OTH)

AF:

0.0700

AC:

4210

AN:

60184

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

5111

10222

15334

20445

25556

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2728

5456

8184

10912

13640

<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:

0.0744

AC:

11314

AN:

152160

Hom.:

450

Cov.:

AF XY:

0.0754

AC XY:

5605

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.0898

AC:

3727

AN:

41506

American (AMR)

AF:

0.0489

AC:

747

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.0415

AC:

144

AN:

3468

East Asian (EAS)

AF:

0.0956

AC:

495

AN:

5176

South Asian (SAS)

AF:

0.0891

AC:

430

AN:

4824

European-Finnish (FIN)

AF:

0.0871

AC:

922

AN:

10580

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0681

AC:

4632

AN:

68028

Other (OTH)

AF:

0.0778

AC:

164

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

543

1086

1630

2173

2716

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

264

396

528

660

<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:

0.0693

Hom.:

118

Bravo

AF:

0.0705

TwinsUK

AF:

0.0574

AC:

213

ALSPAC

AF:

0.0623

AC:

240

ESP6500AA

AF:

0.0906

AC:

246

ESP6500EA

AF:

0.0592

AC:

272

ExAC

AF:

0.0775

AC:

9036

Asia WGS

AF:

0.0840

AC:

290

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (8)

Lynch syndrome 4 (6)

Lynch syndrome (3)

not provided (3)

Hereditary cancer-predisposing syndrome (2)

Endometrial carcinoma (1)

Hereditary nonpolyposis colorectal neoplasms (1)

Lynch syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.84

MetaRNN

Benign

0.0026

MetaSVM

Benign

-0.61

MutationAssessor

Uncertain

2.0

PhyloP100

0.29

PrimateAI

Benign

0.20

PROVEAN

Benign

-1.8

REVEL

Uncertain

0.43

Sift

Benign

0.12

Sift4G

Benign

0.20

Polyphen

0.50

Vest4

0.15

MPC

0.043

ClinPred

0.015

GERP RS

0.77

Varity_R

0.036

gMVP

0.22

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over