Genetic Variant PMS2:p.Met622Ile (chr7-5986899-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.1866G>A(p.Met622Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.019 in 1,614,076 control chromosomes in the GnomAD database, including 403 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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 Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M622V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.016 ( 28 hom., cov: 32)

Exomes 𝑓: 0.019 ( 375 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:29O:1

Conservation

PhyloP100: 2.52

Publications

37 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=0.0026652813).

BP6

Variant 7-5986899-C-T is Benign according to our data. Variant chr7-5986899-C-T is described in ClinVar as Benign. ClinVar VariationId is 41708.Status of the report is reviewed_by_expert_panel, 3 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0158 (2409/152236) while in subpopulation NFE AF = 0.0226 (1535/68006). AF 95% confidence interval is 0.0216. There are 28 homozygotes in GnomAd4. There are 1210 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 28 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.1866G>A	p.Met622Ile	missense	Exon 11 of 15	NP_000526.2	P54278-1
PMS2	NM_001406866.1		c.2052G>A	p.Met684Ile	missense	Exon 12 of 16	NP_001393795.1	A0A8V8TNX6
PMS2	NM_001322014.2		c.1866G>A	p.Met622Ile	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.1866G>A	p.Met622Ile	missense	Exon 11 of 15	ENSP00000265849.7	P54278-1
PMS2	ENST00000382321.5	TSL:1	c.804-3908G>A		intron	N/A	ENSP00000371758.4	P54278-2
PMS2	ENST00000406569.8	TSL:1	n.1678+188G>A		intron	N/A	ENSP00000514464.1	P54278-3

Frequencies

GnomAD3 genomes

AF:

0.0158

AC:

2409

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00314

Gnomad AMI

AF:

0.0418

Gnomad AMR

AF:

0.0119

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00601

Gnomad FIN

AF:

0.0410

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0226

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.0164

AC:

4119

AN:

251440

AF XY:

0.0163

show subpopulations

Gnomad AFR exome

AF:

0.00345

Gnomad AMR exome

AF:

0.00518

Gnomad ASJ exome

AF:

0.0136

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0396

Gnomad NFE exome

AF:

0.0234

Gnomad OTH exome

AF:

0.0140

GnomAD4 exome

AF:

0.0194

AC:

28328

AN:

1461840

Hom.:

375

Cov.:

AF XY:

0.0188

AC XY:

13679

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.00311

AC:

104

AN:

33480

American (AMR)

AF:

0.00525

AC:

235

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0144

AC:

376

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00515

AC:

444

AN:

86250

European-Finnish (FIN)

AF:

0.0390

AC:

2083

AN:

53420

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0217

AC:

24116

AN:

1111968

Other (OTH)

AF:

0.0160

AC:

964

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

1488

2976

4464

5952

7440

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

848

1696

2544

3392

4240

<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:

0.0158

AC:

2409

AN:

152236

Hom.:

Cov.:

AF XY:

0.0163

AC XY:

1210

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.00313

AC:

130

AN:

41560

American (AMR)

AF:

0.0119

AC:

181

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.0112

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00601

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0410

AC:

434

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0226

AC:

1535

AN:

68006

Other (OTH)

AF:

0.0109

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

122

244

366

488

610

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.0202

Hom.:

110

Bravo

AF:

0.0130

TwinsUK

AF:

0.0178

AC:

ALSPAC

AF:

0.0182

AC:

ESP6500AA

AF:

0.00522

AC:

ESP6500EA

AF:

0.0212

AC:

182

ExAC

AF:

0.0176

AC:

2136

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0188

EpiControl

AF:

0.0177

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (10)

Lynch syndrome 4 (7)

Hereditary cancer-predisposing syndrome (5)

not provided (3)

Lynch syndrome (2)

Endometrial carcinoma (1)

Hereditary nonpolyposis colorectal neoplasms (1)

Ovarian neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.089

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.029

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.87

MetaRNN

Benign

0.0027

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

PhyloP100

2.5

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.96

REVEL

Benign

0.090

Sift

Benign

0.25

Sift4G

Benign

0.30

Polyphen

0.0020

Vest4

0.36

MutPred

0.28

Loss of disorder (P = 0.0751)

MPC

0.041

ClinPred

0.018

GERP RS

5.8

Varity_R

0.087

gMVP

0.34

Mutation Taster

=88/12

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

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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