chr7-5977709-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBP6_Very_Strong

The NM_000535.7(PMS2):c.2324A>G(p.Asn775Ser) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N775I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0011 ( 2 hom., cov: 30)

Exomes 𝑓: 0.00027 ( 24 hom. )

Failed GnomAD Quality Control

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:27O:1

Conservation

PhyloP100: 4.85

Publications

31 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15660042).

BP6

Variant 7-5977709-T-C is Benign according to our data. Variant chr7-5977709-T-C is described in ClinVar as Benign. ClinVar VariationId is 36689.Status of the report is reviewed_by_expert_panel, 3 stars.

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.2324A>G	p.Asn775Ser	missense	Exon 14 of 15	NP_000526.2	P54278-1
PMS2	NM_001406866.1		c.2510A>G	p.Asn837Ser	missense	Exon 15 of 16	NP_001393795.1	A0A8V8TNX6
PMS2	NM_001322014.2		c.2357A>G	p.Asn786Ser	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.2324A>G	p.Asn775Ser	missense	Exon 14 of 15	ENSP00000265849.7	P54278-1
PMS2	ENST00000382321.5	TSL:1	c.1121A>G	p.Asn374Ser	missense	Exon 10 of 11	ENSP00000371758.4	P54278-2
PMS2	ENST00000406569.8	TSL:1	n.1684A>G		non_coding_transcript_exon	Exon 12 of 13	ENSP00000514464.1	P54278-3

Frequencies

GnomAD3 genomes

AF:

0.00113

AC:

169

AN:

150216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000613

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00112

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000783

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000289

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00172

Gnomad OTH

AF:

0.00195

GnomAD2 exomes

AF:

0.000252

AC:

AN:

249826

AF XY:

0.000230

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000377

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000382

Gnomad OTH exome

AF:

0.000656

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000268

AC:

390

AN:

1452696

Hom.:

Cov.:

AF XY:

0.000263

AC XY:

190

AN XY:

722712

show subpopulations

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

African (AFR)

AF:

0.000150

AC:

AN:

33268

American (AMR)

AF:

0.000314

AC:

AN:

44586

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26088

East Asian (EAS)

AF:

0.000101

AC:

AN:

39414

South Asian (SAS)

AF:

0.000105

AC:

AN:

85856

European-Finnish (FIN)

AF:

0.000151

AC:

AN:

53052

Middle Eastern (MID)

AF:

0.000349

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.000302

AC:

334

AN:

1104658

Other (OTH)

AF:

0.000233

AC:

AN:

60044

⚠️ 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: 0.263

Heterozygous variant carriers

115

154

192

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00112

AC:

169

AN:

150318

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

AN XY:

73352

show subpopulations

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

African (AFR)

AF:

0.000611

AC:

AN:

40910

American (AMR)

AF:

0.00112

AC:

AN:

15152

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3452

East Asian (EAS)

AF:

0.000785

AC:

AN:

5094

South Asian (SAS)

AF:

0.00

AC:

AN:

4744

European-Finnish (FIN)

AF:

0.000289

AC:

AN:

10390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00172

AC:

116

AN:

67306

Other (OTH)

AF:

0.00193

AC:

AN:

2072

⚠️ 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: 0.317

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:

0.000625

Hom.:

ExAC

AF:

0.000545

AC:

EpiCase

AF:

0.00132

EpiControl

AF:

0.000715

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Lynch syndrome 4 (6)

not specified (7)

Hereditary cancer-predisposing syndrome (4)

not provided (4)

Lynch syndrome (3)

Breast and/or ovarian cancer (1)

Endometrial carcinoma (1)

Hereditary nonpolyposis colorectal neoplasms (1)

Lynch syndrome 1 (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.051

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.022

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.025

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.57

MutationAssessor

Benign

1.5

PhyloP100

4.9

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.33

Sift

Benign

0.22

Sift4G

Benign

0.17

Polyphen

0.76

Vest4

0.39

MVP

0.82

MPC

2.1

ClinPred

0.20

GERP RS

4.6

Varity_R

0.35

gMVP

0.37

Mutation Taster

=82/18

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over