7-5973428-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001406866.1(PMS2):c.2746G>A(p.Ala916Thr) variant causes a missense change. 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. A916S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000022 ( 1 hom., cov: 12)

Exomes 𝑓: 0.000016 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

PMS2
NM_001406866.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: 5.02

Publications

9 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: Likely_benign. The variant received -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.37591857).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406866.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PMS2	NM_000535.7	MANE Select	c.2560G>A	p.Ala854Thr	missense	Exon 15 of 15	NP_000526.2
PMS2	NM_001406866.1		c.2746G>A	p.Ala916Thr	missense	Exon 16 of 16	NP_001393795.1
PMS2	NM_001322014.2		c.2593G>A	p.Ala865Thr	missense	Exon 15 of 15	NP_001308943.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PMS2	ENST00000265849.12	TSL:1 MANE Select	c.2560G>A	p.Ala854Thr	missense	Exon 15 of 15	ENSP00000265849.7
PMS2	ENST00000382321.5	TSL:1	c.1357G>A	p.Ala453Thr	missense	Exon 11 of 11	ENSP00000371758.4
PMS2	ENST00000406569.8	TSL:1	n.*201G>A		non_coding_transcript_exon	Exon 13 of 13	ENSP00000514464.1

Frequencies

GnomAD3 genomes

AF:

0.0000217

AC:

AN:

91998

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000841

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000197

AC:

AN:

203410

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000116

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000337

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000159

AC:

AN:

880376

Hom.:

Cov.:

AF XY:

0.00000882

AC XY:

AN XY:

453450

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

21732

American (AMR)

AF:

0.00

AC:

AN:

35936

Ashkenazi Jewish (ASJ)

AF:

0.0000488

AC:

AN:

20476

East Asian (EAS)

AF:

0.00

AC:

AN:

30804

South Asian (SAS)

AF:

0.00

AC:

AN:

67588

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46164

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3092

European-Non Finnish (NFE)

AF:

0.0000211

AC:

AN:

615088

Other (OTH)

AF:

0.00

AC:

AN:

39496

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.429

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000217

AC:

AN:

92074

Hom.:

Cov.:

AF XY:

0.0000464

AC XY:

AN XY:

43142

show subpopulations

African (AFR)

AF:

0.0000838

AC:

AN:

23858

American (AMR)

AF:

0.00

AC:

AN:

8196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2420

East Asian (EAS)

AF:

0.00

AC:

AN:

2736

South Asian (SAS)

AF:

0.00

AC:

AN:

2294

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

196

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

44980

Other (OTH)

AF:

0.00

AC:

AN:

1186

Alfa

AF:

0.0000440

Hom.:

ExAC

AF:

0.0000263

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (3)

Hereditary nonpolyposis colorectal neoplasms (1)

Lynch syndrome 4 (1)

Lynch syndrome 4;C5399763:Mismatch repair cancer syndrome 1 (1)

Lynch-like syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.065

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.38

MetaSVM

Uncertain

0.23

MutationAssessor

Benign

0.63

PhyloP100

5.0

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.43

Sift

Benign

0.18

Sift4G

Benign

0.093

Polyphen

0.99

Vest4

0.45

MutPred

0.39

Gain of catalytic residue at A854 (P = 0.0679)

MVP

0.90

MPC

3.0

ClinPred

0.87

GERP RS

5.2

Varity_R

0.11

gMVP

0.67

Mutation Taster

=69/31

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over