Genetic Variant PMS2:p.His479Gln (chr7-5987328-G-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000535.7(PMS2):c.1437C>G(p.His479Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00344 in 1,613,972 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. H479D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0055 ( 7 hom., cov: 31)

Exomes 𝑓: 0.0032 ( 18 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:25O:1

Conservation

PhyloP100: 0.199

Publications

27 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0054139197).

BP6

Variant 7-5987328-G-C is Benign according to our data. Variant chr7-5987328-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 41701.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00549 (836/152266) while in subpopulation AFR AF = 0.0097 (403/41560). AF 95% confidence interval is 0.00892. There are 7 homozygotes in GnomAd4. There are 417 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 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.1437C>G	p.His479Gln	missense	Exon 11 of 15	NP_000526.2	P54278-1
PMS2	NM_001406866.1		c.1623C>G	p.His541Gln	missense	Exon 12 of 16	NP_001393795.1	A0A8V8TNX6
PMS2	NM_001322014.2		c.1437C>G	p.His479Gln	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.1437C>G	p.His479Gln	missense	Exon 11 of 15	ENSP00000265849.7	P54278-1
PMS2	ENST00000382321.5	TSL:1	c.804-4337C>G		intron	N/A	ENSP00000371758.4	P54278-2
PMS2	ENST00000406569.8	TSL:1	n.1437C>G		non_coding_transcript_exon	Exon 11 of 13	ENSP00000514464.1	P54278-3

Frequencies

GnomAD3 genomes

AF:

0.00548

AC:

834

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00968

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00223

Gnomad ASJ

AF:

0.00605

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.00373

Gnomad FIN

AF:

0.00990

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00354

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00424

AC:

1067

AN:

251466

AF XY:

0.00432

show subpopulations

Gnomad AFR exome

AF:

0.00898

Gnomad AMR exome

AF:

0.00153

Gnomad ASJ exome

AF:

0.00784

Gnomad EAS exome

AF:

0.000815

Gnomad FIN exome

AF:

0.0111

Gnomad NFE exome

AF:

0.00361

Gnomad OTH exome

AF:

0.00440

GnomAD4 exome

AF:

0.00323

AC:

4718

AN:

1461706

Hom.:

Cov.:

AF XY:

0.00334

AC XY:

2430

AN XY:

727146

show subpopulations

African (AFR)

AF:

0.00920

AC:

308

AN:

33478

American (AMR)

AF:

0.00154

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00708

AC:

185

AN:

26128

East Asian (EAS)

AF:

0.000781

AC:

AN:

39700

South Asian (SAS)

AF:

0.00306

AC:

264

AN:

86250

European-Finnish (FIN)

AF:

0.0106

AC:

567

AN:

53416

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00279

AC:

3103

AN:

1111858

Other (OTH)

AF:

0.00293

AC:

177

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.407

Heterozygous variant carriers

193

385

578

770

963

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

224

336

448

560

<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:

0.00549

AC:

836

AN:

152266

Hom.:

Cov.:

AF XY:

0.00560

AC XY:

417

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.00970

AC:

403

AN:

41560

American (AMR)

AF:

0.00223

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00605

AC:

AN:

3472

East Asian (EAS)

AF:

0.000772

AC:

AN:

5182

South Asian (SAS)

AF:

0.00373

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00990

AC:

105

AN:

10608

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00354

AC:

241

AN:

68026

Other (OTH)

AF:

0.00426

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

118

157

196

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:

0.00345

Hom.:

Bravo

AF:

0.00481

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.00976

AC:

ESP6500EA

AF:

0.00279

AC:

ExAC

AF:

0.00455

AC:

552

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

not specified (7)

Lynch syndrome 4 (5)

Hereditary cancer-predisposing syndrome (4)

Breast and/or ovarian cancer (1)

Hereditary nonpolyposis colorectal neoplasms (1)

Lynch syndrome (1)

Malignant tumor of breast (1)

Ovarian cancer (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.60

CADD

Benign

0.46

(source)

DANN

Benign

0.54

DEOGEN2

Benign

0.051

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0025

LIST_S2

Benign

0.11

MetaRNN

Benign

0.0054

MetaSVM

Benign

-0.75

MutationAssessor

Benign

-1.1

PhyloP100

0.20

PrimateAI

Benign

0.20

PROVEAN

Benign

0.63

REVEL

Benign

0.093

Sift

Benign

0.60

Sift4G

Benign

0.61

Polyphen

0.0

Vest4

0.055

MutPred

0.17

Gain of helix (P = 0.062)

MVP

0.26

MPC

0.036

ClinPred

0.000037

GERP RS

2.2

Varity_R

0.022

gMVP

0.17

Mutation Taster

=98/2

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

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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