Genetic Variant PMS2:p.Glu537Lys (chr7-5987156-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000535.7(PMS2):c.1609G>A(p.Glu537Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000659 in 1,613,950 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E537G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0035 ( 2 hom., cov: 31)

Exomes 𝑓: 0.00036 ( 5 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19

Conservation

PhyloP100: 0.284

Publications

8 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=0.0057940483).

BP6

Variant 7-5987156-C-T is Benign according to our data. Variant chr7-5987156-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00351 (535/152276) while in subpopulation AFR AF = 0.0125 (518/41546). AF 95% confidence interval is 0.0116. There are 2 homozygotes in GnomAd4. There are 258 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR,AD gene

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.1609G>A	p.Glu537Lys	missense	Exon 11 of 15	NP_000526.2	P54278-1
PMS2	NM_001406866.1		c.1795G>A	p.Glu599Lys	missense	Exon 12 of 16	NP_001393795.1	A0A8V8TNX6
PMS2	NM_001322014.2		c.1609G>A	p.Glu537Lys	missense	Exon 11 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.1609G>A	p.Glu537Lys	missense	Exon 11 of 15	ENSP00000265849.7	P54278-1
PMS2	ENST00000382321.5	TSL:1	c.804-4165G>A		intron	N/A	ENSP00000371758.4	P54278-2
PMS2	ENST00000406569.8	TSL:1	n.1609G>A		non_coding_transcript_exon	Exon 11 of 13	ENSP00000514464.1	P54278-3

Frequencies

GnomAD3 genomes

AF:

0.00352

AC:

535

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0125

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000656

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:

0.0000147

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000853

AC:

214

AN:

250784

AF XY:

0.000649

show subpopulations

Gnomad AFR exome

AF:

0.0123

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000362

AC:

529

AN:

1461674

Hom.:

Cov.:

AF XY:

0.000303

AC XY:

220

AN XY:

727160

show subpopulations

African (AFR)

AF:

0.0140

AC:

467

AN:

33474

American (AMR)

AF:

0.000425

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53340

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111898

Other (OTH)

AF:

0.000679

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

119

149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00351

AC:

535

AN:

152276

Hom.:

Cov.:

AF XY:

0.00346

AC XY:

258

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0125

AC:

518

AN:

41546

American (AMR)

AF:

0.000655

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68032

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

104

130

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00209

Hom.:

Bravo

AF:

0.00379

ESP6500AA

AF:

0.0125

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00103

AC:

125

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

Hereditary cancer-predisposing syndrome (3)

Lynch syndrome 4 (3)

not provided (3)

Breast and/or ovarian cancer (1)

Hereditary nonpolyposis colorectal neoplasms (1)

Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.39

CADD

Benign

9.0

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.092

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.56

MetaRNN

Benign

0.0058

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.4

PhyloP100

0.28

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.74

REVEL

Benign

0.25

Sift

Benign

0.50

Sift4G

Benign

0.73

Polyphen

0.0010

Vest4

0.24

MVP

0.52

MPC

0.040

ClinPred

0.0059

GERP RS

3.7

Varity_R

0.029

gMVP

0.27

Mutation Taster

=96/4

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

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