7-5977745-T-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_000535.7(PMS2):c.2288A>G(p.Glu763Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000106 in 1,605,912 control chromosomes in the GnomAD database, including 3 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. E763K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000027 ( 1 hom., cov: 30)

Exomes 𝑓: 0.0000089 ( 2 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:1

Conservation

PhyloP100: 5.95

Publications

5 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
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: Labcorp Genetics (formerly Invitae), G2P
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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.4029799).

BS2

High Homozygotes in GnomAdExome4 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.2288A>G	p.Glu763Gly	missense	Exon 14 of 15	NP_000526.2	P54278-1
PMS2	NM_001406866.1		c.2474A>G	p.Glu825Gly	missense	Exon 15 of 16	NP_001393795.1	A0A8V8TNX6
PMS2	NM_001322014.2		c.2321A>G	p.Glu774Gly	missense	Exon 14 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.2288A>G	p.Glu763Gly	missense	Exon 14 of 15	ENSP00000265849.7	P54278-1
PMS2	ENST00000382321.5	TSL:1	c.1085A>G	p.Glu362Gly	missense	Exon 10 of 11	ENSP00000371758.4	P54278-2
PMS2	ENST00000406569.8	TSL:1	n.1679-31A>G		intron	N/A	ENSP00000514464.1	P54278-3

Frequencies

GnomAD3 genomes

AF:

0.0000265

AC:

AN:

150730

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000592

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

250084

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000893

AC:

AN:

1455182

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

723944

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33276

American (AMR)

AF:

0.00

AC:

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26090

East Asian (EAS)

AF:

0.00

AC:

AN:

39430

South Asian (SAS)

AF:

0.00

AC:

AN:

85868

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53014

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

1106964

Other (OTH)

AF:

0.00

AC:

AN:

60118

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.431

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000265

AC:

AN:

150730

Hom.:

Cov.:

AF XY:

0.0000272

AC XY:

AN XY:

73484

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40956

American (AMR)

AF:

0.00

AC:

AN:

15168

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5120

South Asian (SAS)

AF:

0.00

AC:

AN:

4752

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10432

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000592

AC:

AN:

67546

Other (OTH)

AF:

0.00

AC:

AN:

2064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000477

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000826

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Hereditary cancer-predisposing syndrome (3)

Lynch syndrome 4 (2)

Hereditary nonpolyposis colorectal neoplasms (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.027

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.40

MetaSVM

Benign

-0.29

MutationAssessor

Benign

1.9

PhyloP100

6.0

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-4.3

REVEL

Uncertain

0.37

Sift

Uncertain

0.018

Sift4G

Uncertain

0.039

Polyphen

0.0080

Vest4

0.52

MVP

0.86

MPC

2.8

ClinPred

0.93

GERP RS

5.8

BranchPoint Hunter

3.0

Varity_R

0.40

gMVP

0.59

Mutation Taster

=27/73

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over