Genetic Variant PMS1:c.418+69_418+70dupAA (chr2-189805813-T-TAA) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001321049.2(PMS1):c.487_488dupAA(p.Leu164SerfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000226 in 1,383,590 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 25)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

PMS1
NM_001321049.2 frameshift

Scores

Not classified

Clinical Significance

Not reported in ClinVar

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: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 17 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001321049.2. 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+69_418+70dupAA		intron	N/A	NP_000525.1	P54277-1
PMS1	NM_001321049.2		c.487_488dupAA	p.Leu164SerfsTer15	frameshift	Exon 4 of 4	NP_001307978.1	E9PC40
PMS1	NM_001321045.2		c.418+69_418+70dupAA		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+69_418+70dupAA	intron	N/A	ENSP00000406490.3	P54277-1
PMS1	ENST00000374826.8	TSL:1	c.418+69_418+70dupAA	intron	N/A	ENSP00000363959.4	Q5XG96
PMS1	ENST00000424059.1	TSL:1	n.418+69_418+70dupAA	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000114

AC:

AN:

148958

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000671

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000102

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000598

Gnomad OTH

AF:

0.000493

GnomAD2 exomes

AF:

0.000473

AC:

AN:

133226

AF XY:

0.000339

show subpopulations

Gnomad AFR exome

AF:

0.000749

Gnomad AMR exome

AF:

0.000887

Gnomad ASJ exome

AF:

0.000178

Gnomad EAS exome

AF:

0.000676

Gnomad FIN exome

AF:

0.000141

Gnomad NFE exome

AF:

0.000382

Gnomad OTH exome

AF:

0.00123

GnomAD4 exome

AF:

0.000239

AC:

295

AN:

1234632

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

132

AN XY:

613202

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000492

AC:

AN:

28466

American (AMR)

AF:

0.000713

AC:

AN:

36476

Ashkenazi Jewish (ASJ)

AF:

0.000138

AC:

AN:

21766

East Asian (EAS)

AF:

0.000240

AC:

AN:

33398

South Asian (SAS)

AF:

0.0000712

AC:

AN:

70178

European-Finnish (FIN)

AF:

0.0000670

AC:

AN:

44788

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5056

European-Non Finnish (NFE)

AF:

0.000240

AC:

227

AN:

943980

Other (OTH)

AF:

0.000178

AC:

AN:

50524

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.299

Heterozygous variant carriers

111

139

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:

0.000114

AC:

AN:

148958

Hom.:

Cov.:

AF XY:

0.000152

AC XY:

AN XY:

72558

show subpopulations

African (AFR)

AF:

0.0000246

AC:

AN:

40732

American (AMR)

AF:

0.000671

AC:

AN:

14898

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3436

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.00

AC:

AN:

4706

European-Finnish (FIN)

AF:

0.000102

AC:

AN:

9850

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000598

AC:

AN:

66944

Other (OTH)

AF:

0.000493

AC:

AN:

2030

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

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:

0.00101

Hom.:

151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.61

Mutation Taster

=148/52

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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2-189805813-TAAA-TAAAAA

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