NM_000534.5:c.1609G>A

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.1609G>A(p.Glu537Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00243 in 1,607,300 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 6 hom. )

Consequence

PMS1
NM_000534.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: 3.85

Publications

13 publications found

Variant links:

COSMIC-nc: COSV59717585

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=0.0070312917).

BP6

Variant 2-189854881-G-A is Benign according to our data. Variant chr2-189854881-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 135055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 313 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS1	NM_000534.5 link	c.1609G>A	p.Glu537Lys	missense_variant	Exon 9 of 13	ENST00000441310.7	NP_000525.1	P54277-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS1	ENST00000441310.7 link	c.1609G>A	p.Glu537Lys	missense_variant	Exon 9 of 13	1	NM_000534.5	ENSP00000406490.3		P54277-1

Frequencies

GnomAD3 genomes

AF:

0.00207

AC:

314

AN:

152020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000749

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00282

Gnomad ASJ

AF:

0.00952

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00293

Gnomad OTH

AF:

0.00336

GnomAD2 exomes

AF:

0.00219

AC:

546

AN:

249024

AF XY:

0.00224

show subpopulations

Gnomad AFR exome

AF:

0.000513

Gnomad AMR exome

AF:

0.00297

Gnomad ASJ exome

AF:

0.00988

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.00280

Gnomad OTH exome

AF:

0.00248

GnomAD4 exome

AF:

0.00247

AC:

3591

AN:

1455162

Hom.:

Cov.:

AF XY:

0.00244

AC XY:

1764

AN XY:

724140

show subpopulations

African (AFR)

AF:

0.000542

AC:

AN:

33210

American (AMR)

AF:

0.00344

AC:

153

AN:

44508

Ashkenazi Jewish (ASJ)

AF:

0.0114

AC:

297

AN:

26060

East Asian (EAS)

AF:

0.00

AC:

AN:

39606

South Asian (SAS)

AF:

0.000186

AC:

AN:

85798

European-Finnish (FIN)

AF:

0.000169

AC:

AN:

53376

Middle Eastern (MID)

AF:

0.00244

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00266

AC:

2949

AN:

1106724

Other (OTH)

AF:

0.00224

AC:

135

AN:

60134

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

166

331

497

662

828

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

228

342

456

570

<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:

0.00206

AC:

313

AN:

152138

Hom.:

Cov.:

AF XY:

0.00194

AC XY:

144

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.000747

AC:

AN:

41516

American (AMR)

AF:

0.00282

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00952

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0000944

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00291

AC:

198

AN:

67982

Other (OTH)

AF:

0.00332

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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:

0.00292

Hom.:

Bravo

AF:

0.00214

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00443

AC:

ExAC

AF:

0.00188

AC:

228

EpiCase

AF:

0.00289

EpiControl

AF:

0.00356

ClinVar

Significance: Likely benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PMS1 p.Glu361Lys variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs151325573) and ClinVar (classified as a VUS by Illumina and Genomic Research Center, Shahid Beheshti University of Medical Sciences for Lynch Syndrome). The variant was identified in control databases in 596 of 280400 chromosomes (3 homozygous) at a frequency of 0.002126 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 101 of 10314 chromosomes (freq: 0.009793), Latino in 103 of 35214 chromosomes (freq: 0.002925), European (non-Finnish) in 354 of 128070 chromosomes (freq: 0.002764), Other in 18 of 7128 chromosomes (freq: 0.002525), African in 13 of 24308 chromosomes (freq: 0.000535), South Asian in 6 of 30404 chromosomes (freq: 0.000197) and European (Finnish) in 1 of 25054 chromosomes (freq: 0.00004); it was not observed in the East Asian population. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Glu361 residue is not conserved in mammals and four out of five computational analyses (SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

not specified

Benign:1Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Jul 27, 2021

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary breast ovarian cancer syndrome

Benign:1

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.070

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.016

T;T;T;T;T;.;.;.;.

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.92

D;.;D;D;D;D;D;D;D

M_CAP

Benign

0.066

MetaRNN

Benign

0.0070

T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.48

MutationAssessor

Uncertain

2.5

.;.;.;.;M;.;M;.;.

PhyloP100

3.8

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.97

.;.;N;.;N;N;N;N;N

REVEL

Uncertain

0.43

Sift

Benign

0.050

.;.;D;.;T;T;T;D;T

Sift4G

Benign

0.24

.;T;T;T;T;T;T;T;T

Polyphen

0.93, 0.89

.;.;.;P;P;.;.;.;.

Vest4

0.27, 0.27, 0.32, 0.30, 0.34, 0.29

MVP

0.99

MPC

0.16

ClinPred

0.039

GERP RS

5.0

Varity_R

0.073

gMVP

0.28

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over