Genetic Variant NM_000534.5:c.418+70dupA (chr2-189805813-T-TA) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBA1

The NM_000534.5(PMS1):c.418+70dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 1,353,866 control chromosomes in the GnomAD database, including 9,570 homozygotes. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.23 ( 3958 hom., cov: 25)

Exomes 𝑓: 0.21 ( 5612 hom. )

Consequence

PMS1
NM_000534.5 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.609

Publications

7 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 -10 ACMG points.

BP6

Variant 2-189805813-T-TA is Benign according to our data. Variant chr2-189805813-T-TA is described in ClinVar as Benign. ClinVar VariationId is 1228750.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.285 is higher than 0.05.

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.418+70dupA		intron	N/A	NP_000525.1	P54277-1
PMS1	NM_001321049.2		c.488dupA	p.Leu164ValfsTer4	frameshift	Exon 4 of 4	NP_001307978.1	E9PC40
PMS1	NM_001321045.2		c.418+70dupA		intron	N/A	NP_001307974.1	P54277-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PMS1	ENST00000441310.7	TSL:1 MANE Select	c.418+70dupA	intron	N/A	ENSP00000406490.3	P54277-1
PMS1	ENST00000374826.8	TSL:1	c.418+70dupA	intron	N/A	ENSP00000363959.4	Q5XG96
PMS1	ENST00000424059.1	TSL:1	n.418+70dupA	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.228

AC:

34013

AN:

148872

Hom.:

3953

Cov.:

show subpopulations

Gnomad AFR

AF:

0.290

Gnomad AMI

AF:

0.136

Gnomad AMR

AF:

0.252

Gnomad ASJ

AF:

0.219

Gnomad EAS

AF:

0.229

Gnomad SAS

AF:

0.124

Gnomad FIN

AF:

0.204

Gnomad MID

AF:

0.255

Gnomad NFE

AF:

0.199

Gnomad OTH

AF:

0.215

GnomAD2 exomes

AF:

0.278

AC:

37092

AN:

133226

AF XY:

0.276

show subpopulations

Gnomad AFR exome

AF:

0.336

Gnomad AMR exome

AF:

0.324

Gnomad ASJ exome

AF:

0.310

Gnomad EAS exome

AF:

0.305

Gnomad FIN exome

AF:

0.259

Gnomad NFE exome

AF:

0.264

Gnomad OTH exome

AF:

0.305

GnomAD4 exome

AF:

0.208

AC:

250808

AN:

1204904

Hom.:

5612

Cov.:

AF XY:

0.206

AC XY:

123130

AN XY:

598466

show subpopulations

African (AFR)

AF:

0.293

AC:

8196

AN:

28000

American (AMR)

AF:

0.236

AC:

8396

AN:

35544

Ashkenazi Jewish (ASJ)

AF:

0.230

AC:

4893

AN:

21272

East Asian (EAS)

AF:

0.238

AC:

7796

AN:

32696

South Asian (SAS)

AF:

0.137

AC:

9280

AN:

67756

European-Finnish (FIN)

AF:

0.213

AC:

9342

AN:

43834

Middle Eastern (MID)

AF:

0.241

AC:

1201

AN:

4982

European-Non Finnish (NFE)

AF:

0.208

AC:

191365

AN:

921544

Other (OTH)

AF:

0.210

AC:

10339

AN:

49276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

Heterozygous variant carriers

12885

25769

38654

51538

64423

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7328

14656

21984

29312

36640

<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:

0.228

AC:

34036

AN:

148962

Hom.:

3958

Cov.:

AF XY:

0.226

AC XY:

16445

AN XY:

72616

show subpopulations

African (AFR)

AF:

0.290

AC:

11821

AN:

40822

American (AMR)

AF:

0.252

AC:

3758

AN:

14898

Ashkenazi Jewish (ASJ)

AF:

0.219

AC:

753

AN:

3436

East Asian (EAS)

AF:

0.230

AC:

1179

AN:

5132

South Asian (SAS)

AF:

0.122

AC:

575

AN:

4694

European-Finnish (FIN)

AF:

0.204

AC:

2009

AN:

9828

Middle Eastern (MID)

AF:

0.252

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.199

AC:

13301

AN:

66916

Other (OTH)

AF:

0.217

AC:

444

AN:

2044

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1277

2554

3831

5108

6385

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

352

704

1056

1408

1760

<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:

0.140

Hom.:

151

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.61

Mutation Taster

=183/17

polymorphism (auto)

(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

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