dbSNP rs2066459: PMS1:p.Arg202Lys (chr2-189843986-G-A) – ACMG Classification: Benign (-20 pts)

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.605G>A(p.Arg202Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,613,946 control chromosomes in the GnomAD database, including 169 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0079 ( 11 hom., cov: 31)

Exomes 𝑓: 0.012 ( 158 hom. )

Consequence

PMS1
NM_000534.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: 2.33

Publications

27 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:

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=0.005322993).

BP6

Variant 2-189843986-G-A is Benign according to our data. Variant chr2-189843986-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 135046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00788 (1201/152318) while in subpopulation SAS AF = 0.0207 (100/4824). AF 95% confidence interval is 0.0174. There are 11 homozygotes in GnomAd4. There are 584 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 1201 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	UniProt
PMS1	NM_000534.5	MANE Select	c.605G>A	p.Arg202Lys	missense	Exon 6 of 13	NP_000525.1	P54277-1
PMS1	NM_001321045.2		c.605G>A	p.Arg202Lys	missense	Exon 7 of 14	NP_001307974.1	P54277-1
PMS1	NM_001321047.2		c.605G>A	p.Arg202Lys	missense	Exon 6 of 13	NP_001307976.1	P54277-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PMS1	ENST00000441310.7	TSL:1 MANE Select	c.605G>A	p.Arg202Lys	missense	Exon 6 of 13	ENSP00000406490.3	P54277-1
PMS1	ENST00000409593.5	TSL:1	c.55-8669G>A		intron	N/A	ENSP00000387169.1	P54277-4
PMS1	ENST00000424059.1	TSL:1	n.583-8669G>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00791

AC:

1204

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00191

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00785

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0209

Gnomad FIN

AF:

0.00198

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0119

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.0113

AC:

2842

AN:

251238

AF XY:

0.0122

show subpopulations

Gnomad AFR exome

AF:

0.00178

Gnomad AMR exome

AF:

0.00645

Gnomad ASJ exome

AF:

0.0141

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00254

Gnomad NFE exome

AF:

0.0138

Gnomad OTH exome

AF:

0.0155

GnomAD4 exome

AF:

0.0117

AC:

17167

AN:

1461628

Hom.:

158

Cov.:

AF XY:

0.0120

AC XY:

8742

AN XY:

727114

show subpopulations

African (AFR)

AF:

0.00248

AC:

AN:

33466

American (AMR)

AF:

0.00691

AC:

309

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0133

AC:

348

AN:

26122

East Asian (EAS)

AF:

0.000101

AC:

AN:

39664

South Asian (SAS)

AF:

0.0236

AC:

2034

AN:

86254

European-Finnish (FIN)

AF:

0.00294

AC:

157

AN:

53372

Middle Eastern (MID)

AF:

0.0239

AC:

138

AN:

5762

European-Non Finnish (NFE)

AF:

0.0120

AC:

13354

AN:

1111890

Other (OTH)

AF:

0.0123

AC:

740

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

822

1644

2467

3289

4111

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

486

972

1458

1944

2430

<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:

0.00788

AC:

1201

AN:

152318

Hom.:

Cov.:

AF XY:

0.00784

AC XY:

584

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00190

AC:

AN:

41566

American (AMR)

AF:

0.00777

AC:

119

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

AN:

3470

East Asian (EAS)

AF:

0.000578

AC:

AN:

5186

South Asian (SAS)

AF:

0.0207

AC:

100

AN:

4824

European-Finnish (FIN)

AF:

0.00198

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0120

AC:

813

AN:

68026

Other (OTH)

AF:

0.0104

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

122

184

245

306

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:

0.0123

Hom.:

Bravo

AF:

0.00778

TwinsUK

AF:

0.00971

AC:

ALSPAC

AF:

0.0106

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.0120

AC:

103

ExAC

AF:

0.0120

AC:

1461

Asia WGS

AF:

0.00953

AC:

AN:

3478

EpiCase

AF:

0.0158

EpiControl

AF:

0.0146

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Hereditary breast ovarian cancer syndrome (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.0097

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.014

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.57

MetaRNN

Benign

0.0053

MetaSVM

Benign

-0.75

MutationAssessor

Benign

0.55

PhyloP100

2.3

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.39

REVEL

Benign

0.15

Sift

Benign

0.59

Sift4G

Benign

0.43

Polyphen

0.0010

Vest4

0.064

MPC

0.062

ClinPred

0.011

GERP RS

5.1

Varity_R

0.12

gMVP

0.32

Mutation Taster

=99/1

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

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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