chr7-5977596-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_000535.7(PMS2):c.2437C>T(p.Arg813Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000613 in 1,565,522 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic 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. R813L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000052 ( 1 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:13B:2

Conservation

PhyloP100: 5.11

Publications

11 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: Uncertain_significance. The variant received 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.815

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.2437C>T	p.Arg813Trp	missense	Exon 14 of 15	NP_000526.2	P54278-1
PMS2	NM_001406866.1		c.2623C>T	p.Arg875Trp	missense	Exon 15 of 16	NP_001393795.1	A0A8V8TNX6
PMS2	NM_001322014.2		c.2470C>T	p.Arg824Trp	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.2437C>T	p.Arg813Trp	missense	Exon 14 of 15	ENSP00000265849.7	P54278-1
PMS2	ENST00000382321.5	TSL:1	c.1234C>T	p.Arg412Trp	missense	Exon 10 of 11	ENSP00000371758.4	P54278-2
PMS2	ENST00000406569.8	TSL:1	n.*78C>T		non_coding_transcript_exon	Exon 12 of 13	ENSP00000514464.1	P54278-3

Frequencies

GnomAD3 genomes

AF:

0.000148

AC:

AN:

148678

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000468

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000200

Gnomad SAS

AF:

0.000215

Gnomad FIN

AF:

0.0000993

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000107

AC:

AN:

206338

AF XY:

0.0000798

show subpopulations

Gnomad AFR exome

AF:

0.000238

Gnomad AMR exome

AF:

0.0000325

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000381

Gnomad FIN exome

AF:

0.000107

Gnomad NFE exome

AF:

0.0000116

Gnomad OTH exome

AF:

0.000568

GnomAD4 exome

AF:

0.0000522

AC:

AN:

1416744

Hom.:

Cov.:

AF XY:

0.0000439

AC XY:

AN XY:

705676

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000458

AC:

AN:

32770

American (AMR)

AF:

0.0000227

AC:

AN:

44090

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25858

East Asian (EAS)

AF:

0.000231

AC:

AN:

39008

South Asian (SAS)

AF:

0.000225

AC:

AN:

84588

European-Finnish (FIN)

AF:

0.0000381

AC:

AN:

52452

Middle Eastern (MID)

AF:

0.000181

AC:

AN:

5538

European-Non Finnish (NFE)

AF:

0.0000196

AC:

AN:

1073592

Other (OTH)

AF:

0.000102

AC:

AN:

58848

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.365

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000148

AC:

AN:

148778

Hom.:

Cov.:

AF XY:

0.000138

AC XY:

AN XY:

72394

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000467

AC:

AN:

40706

American (AMR)

AF:

0.00

AC:

AN:

14904

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3428

East Asian (EAS)

AF:

0.000201

AC:

AN:

4976

South Asian (SAS)

AF:

0.000215

AC:

AN:

4658

European-Finnish (FIN)

AF:

0.0000993

AC:

AN:

10070

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66786

Other (OTH)

AF:

0.00

AC:

AN:

2048

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.316

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

ESP6500AA

AF:

0.000867

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000673

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Hereditary cancer-predisposing syndrome (3)

Lynch syndrome 4 (2)

not specified (2)

Hereditary cancer (1)

Hereditary nonpolyposis colorectal neoplasms (1)

Lynch syndrome (1)

Ovarian cancer (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.51

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

1.0

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.82

MetaSVM

Uncertain

0.61

MutationAssessor

Pathogenic

3.8

PhyloP100

5.1

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-7.0

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.99

MVP

0.96

MPC

3.3

ClinPred

0.97

GERP RS

4.8

Varity_R

0.95

gMVP

0.91

Mutation Taster

=8/92

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over