Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000534.5(PMS1):c.2417C>G(p.Thr806Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,596,392 control chromosomes in the GnomAD database, including 29 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 Benign (★★).

Frequency

Genomes: 𝑓 0.0065 ( 17 hom., cov: 32)

Exomes 𝑓: 0.00070 ( 12 hom. )

Consequence

PMS1
NM_000534.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.569

Publications

11 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0054065287).

BP6

Variant 2-189867873-C-G is Benign according to our data. Variant chr2-189867873-C-G is described in ClinVar as Benign. ClinVar VariationId is 135047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00654 (996/152302) while in subpopulation AFR AF = 0.0221 (920/41570). AF 95% confidence interval is 0.0209. There are 17 homozygotes in GnomAd4. There are 486 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 996 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.2417C>G	p.Thr806Ser	missense	Exon 11 of 13	NP_000525.1
PMS1	NM_001321045.2		c.2417C>G	p.Thr806Ser	missense	Exon 12 of 14	NP_001307974.1
PMS1	NM_001321047.2		c.2417C>G	p.Thr806Ser	missense	Exon 11 of 13	NP_001307976.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PMS1	ENST00000441310.7	TSL:1 MANE Select	c.2417C>G	p.Thr806Ser	missense	Exon 11 of 13	ENSP00000406490.3
PMS1	ENST00000409593.5	TSL:1	c.1286C>G	p.Thr429Ser	missense	Exon 5 of 7	ENSP00000387169.1
PMS1	ENST00000424059.1	TSL:1	n.1971+3899C>G		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00654

AC:

996

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0222

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00622

GnomAD2 exomes

AF:

0.00191

AC:

480

AN:

251142

AF XY:

0.00144

show subpopulations

Gnomad AFR exome

AF:

0.0229

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00261

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000881

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000700

AC:

1011

AN:

1444090

Hom.:

Cov.:

AF XY:

0.000596

AC XY:

429

AN XY:

719722

show subpopulations

African (AFR)

AF:

0.0218

AC:

721

AN:

33126

American (AMR)

AF:

0.000940

AC:

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26002

East Asian (EAS)

AF:

0.00121

AC:

AN:

39542

South Asian (SAS)

AF:

0.000908

AC:

AN:

85876

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.000523

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.0000146

AC:

AN:

1096038

Other (OTH)

AF:

0.00173

AC:

103

AN:

59692

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

103

155

206

258

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.00654

AC:

996

AN:

152302

Hom.:

Cov.:

AF XY:

0.00653

AC XY:

486

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0221

AC:

920

AN:

41570

American (AMR)

AF:

0.00288

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00154

AC:

AN:

5188

South Asian (SAS)

AF:

0.000622

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68022

Other (OTH)

AF:

0.00616

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

136

182

227

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.000953

Hom.:

Bravo

AF:

0.00722

ESP6500AA

AF:

0.0220

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00224

AC:

272

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.31

CADD

Benign

3.8

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.011

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.58

MetaRNN

Benign

0.0054

MetaSVM

Benign

-0.43

MutationAssessor

Benign

0.74

PhyloP100

-0.57

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.37

REVEL

Benign

0.050

Sift

Benign

0.64

Sift4G

Benign

0.37

Polyphen

0.0050

Vest4

0.15

MutPred

0.20

Loss of sheet (P = 0.0315)

MVP

0.97

MPC

0.056

ClinPred

0.0021

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.034

gMVP

0.25

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

rs55859858

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over