chr2-189863781-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000534.5(PMS1):c.1895A>G(p.Asn632Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000324 in 1,608,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

PMS1
NM_000534.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: 5.20

Publications

6 publications found

Variant links:

Genes affected

PMS1 (HGNC:9121): (PMS1 homolog 1, mismatch repair system component) This gene encodes a protein belonging to the DNA mismatch repair mutL/hexB family. This protein is thought to be involved in the repair of DNA mismatches, and it can form heterodimers with MLH1, a known DNA mismatch repair protein. Mutations in this gene cause hereditary nonpolyposis colorectal cancer type 3 (HNPCC3) either alone or in combination with mutations in other genes involved in the HNPCC phenotype, which is also known as Lynch syndrome. [provided by RefSeq, Jul 2008]

PMS1 Gene-Disease associations (from GenCC):

Lynch syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

PMS1 links:

ENSG00000300477 (HGNC:):

ENSG00000300477 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005708903).

BP6

Variant 2-189863781-A-G is Benign according to our data. Variant chr2-189863781-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 135058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 258 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000534.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PMS1	NM_000534.5	MANE Select	c.1895A>G	p.Asn632Ser	missense	Exon 10 of 13	NP_000525.1
PMS1	NM_001321045.2		c.1895A>G	p.Asn632Ser	missense	Exon 11 of 14	NP_001307974.1
PMS1	NM_001321047.2		c.1895A>G	p.Asn632Ser	missense	Exon 10 of 13	NP_001307976.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PMS1	ENST00000441310.7	TSL:1 MANE Select	c.1895A>G	p.Asn632Ser	missense	Exon 10 of 13	ENSP00000406490.3
PMS1	ENST00000424059.1	TSL:1	n.1778A>G		non_coding_transcript_exon	Exon 8 of 9
PMS1	ENST00000409593.5	TSL:1	c.1212-4018A>G		intron	N/A	ENSP00000387169.1

Frequencies

GnomAD3 genomes

AF:

0.00169

AC:

257

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00587

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000412

AC:

103

AN:

250258

AF XY:

0.000251

show subpopulations

Gnomad AFR exome

AF:

0.00531

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000443

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000181

AC:

263

AN:

1455784

Hom.:

Cov.:

AF XY:

0.000153

AC XY:

111

AN XY:

724710

show subpopulations

African (AFR)

AF:

0.00588

AC:

196

AN:

33344

American (AMR)

AF:

0.000403

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26088

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39648

South Asian (SAS)

AF:

0.00

AC:

AN:

86094

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.000521

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0000271

AC:

AN:

1106552

Other (OTH)

AF:

0.000249

AC:

AN:

60184

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00169

AC:

258

AN:

152306

Hom.:

Cov.:

AF XY:

0.00165

AC XY:

123

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00587

AC:

244

AN:

41552

American (AMR)

AF:

0.000327

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68028

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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:

0.000658

Hom.:

Bravo

AF:

0.00178

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000544

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1Other:1

Mar 06, 2020

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

not provided

Benign:1

Oct 16, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.85

M_CAP

Benign

0.084

MetaRNN

Benign

0.0057

MetaSVM

Pathogenic

0.92

MutationAssessor

Uncertain

2.0

PhyloP100

5.2

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.3

REVEL

Benign

0.059

Sift

Uncertain

0.015

Sift4G

Benign

0.14

Polyphen

0.25

Vest4

0.19

MVP

0.99

MPC

0.095

ClinPred

0.020

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.17

gMVP

0.084

Mutation Taster

=79/21

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over