7-5977683-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000535.7(PMS2):c.2350G>A(p.Asp784Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000618 in 1,606,010 control chromosomes in the GnomAD database, including 33 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. D784H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0020 ( 6 hom., cov: 30)

Exomes 𝑓: 0.00047 ( 27 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:14

Conservation

PhyloP100: 7.90

Publications

13 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0129443705).

BP6

Variant 7-5977683-C-T is Benign according to our data. Variant chr7-5977683-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127780.

BS2

High Homozygotes in GnomAd4 at 6 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.2350G>A	p.Asp784Asn	missense	Exon 14 of 15	NP_000526.2	P54278-1
PMS2	NM_001406866.1		c.2536G>A	p.Asp846Asn	missense	Exon 15 of 16	NP_001393795.1	A0A8V8TNX6
PMS2	NM_001322014.2		c.2383G>A	p.Asp795Asn	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.2350G>A	p.Asp784Asn	missense	Exon 14 of 15	ENSP00000265849.7	P54278-1
PMS2	ENST00000382321.5	TSL:1	c.1147G>A	p.Asp383Asn	missense	Exon 10 of 11	ENSP00000371758.4	P54278-2
PMS2	ENST00000406569.8	TSL:1	n.1710G>A		non_coding_transcript_exon	Exon 12 of 13	ENSP00000514464.1	P54278-3

Frequencies

GnomAD3 genomes

AF:

0.00198

AC:

298

AN:

150166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00625

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000728

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000197

Gnomad SAS

AF:

0.00529

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000445

Gnomad OTH

AF:

0.00146

GnomAD2 exomes

AF:

0.00114

AC:

285

AN:

250126

AF XY:

0.00115

show subpopulations

Gnomad AFR exome

AF:

0.00685

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000709

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000475

AC:

691

AN:

1455742

Hom.:

Cov.:

AF XY:

0.000548

AC XY:

397

AN XY:

724190

show subpopulations

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

African (AFR)

AF:

0.00698

AC:

232

AN:

33258

American (AMR)

AF:

0.000336

AC:

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26096

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39460

South Asian (SAS)

AF:

0.00420

AC:

361

AN:

85876

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53074

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.0000208

AC:

AN:

1107414

Other (OTH)

AF:

0.000848

AC:

AN:

60138

⚠️ 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

130

162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00200

AC:

301

AN:

150268

Hom.:

Cov.:

AF XY:

0.00184

AC XY:

135

AN XY:

73296

show subpopulations

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

African (AFR)

AF:

0.00631

AC:

258

AN:

40914

American (AMR)

AF:

0.000727

AC:

AN:

15126

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3452

East Asian (EAS)

AF:

0.000197

AC:

AN:

5072

South Asian (SAS)

AF:

0.00529

AC:

AN:

4722

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10324

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000445

AC:

AN:

67376

Other (OTH)

AF:

0.00145

AC:

AN:

2076

⚠️ 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: 0.350

Heterozygous variant carriers

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:

0.00121

Hom.:

ESP6500AA

AF:

0.00615

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00140

AC:

170

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Lynch syndrome 4 (5)

not specified (4)

Hereditary cancer-predisposing syndrome (3)

not provided (2)

Breast and/or ovarian cancer (1)

Hereditary nonpolyposis colorectal neoplasms (1)

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

Malignant tumor of breast (1)

PMS2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.28

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.21

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

MetaRNN

Benign

0.013

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

1.7

PhyloP100

7.9

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.35

Sift

Benign

0.077

Sift4G

Uncertain

0.013

Polyphen

0.98

Vest4

0.56

MVP

0.87

MPC

3.1

ClinPred

0.038

GERP RS

5.8

Varity_R

0.40

gMVP

0.46

Mutation Taster

=11/89

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