7-5997426-GAAAAAAA-GAAAAAAAAA

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_000535.7(PMS2):c.706-5_706-4dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene PMS2 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0032 ( 0 hom. )

Consequence

PMS2
NM_000535.7 splice_region, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 0.187

Publications

10 publications found

Variant links:

Genes affected

PMS2 (HGNC:9122): (PMS1 homolog 2, mismatch repair system component) The protein encoded by this gene is a key component of the mismatch repair system that functions to correct DNA mismatches and small insertions and deletions that can occur during DNA replication and homologous recombination. This protein forms heterodimers with the gene product of the mutL homolog 1 (MLH1) gene to form the MutL-alpha heterodimer. The MutL-alpha heterodimer possesses an endonucleolytic activity that is activated following recognition of mismatches and insertion/deletion loops by the MutS-alpha and MutS-beta heterodimers, and is necessary for removal of the mismatched DNA. There is a DQHA(X)2E(X)4E motif found at the C-terminus of the protein encoded by this gene that forms part of the active site of the nuclease. Mutations in this gene have been associated with hereditary nonpolyposis colorectal cancer (HNPCC; also known as Lynch syndrome) and Turcot syndrome. [provided by RefSeq, Apr 2016]

PMS2 Gene-Disease associations (from GenCC):

Lynch syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Lynch syndrome 4
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
mismatch repair cancer syndrome 1
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
mismatch repair cancer syndrome 4
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
malignant pancreatic neoplasm
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
ovarian cancer
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
Muir-Torre syndrome
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
rhabdomyosarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
breast cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
prostate cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

PMS2 links:

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ACMG classification

Specifications for PMS2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP6

Variant 7-5997426-G-GAA is Benign according to our data. Variant chr7-5997426-G-GAA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1802741.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000535.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PMS2	NM_000535.7	MANE Select	c.706-5_706-4dupTT	splice_region intron	N/A	NP_000526.2	P54278-1
PMS2	NM_001406866.1		c.892-5_892-4dupTT	splice_region intron	N/A	NP_001393795.1	A0A8V8TNX6
PMS2	NM_001322014.2		c.706-5_706-4dupTT	splice_region intron	N/A	NP_001308943.1	A0A8V8TQ50

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PMS2	ENST00000265849.12	TSL:1 MANE Select	c.706-4_706-3insTT	splice_region intron	N/A	ENSP00000265849.7	P54278-1
PMS2	ENST00000382321.5	TSL:1	c.706-4_706-3insTT	splice_region intron	N/A	ENSP00000371758.4	P54278-2
PMS2	ENST00000406569.8	TSL:1	n.706-4_706-3insTT	splice_region intron	N/A	ENSP00000514464.1	P54278-3

Frequencies

GnomAD3 genomes

AF:

0.000188

AC:

AN:

133228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000115

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000152

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000137

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000287

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00345

AC:

499

AN:

144514

AF XY:

0.00361

show subpopulations

Gnomad AFR exome

AF:

0.00314

Gnomad AMR exome

AF:

0.00474

Gnomad ASJ exome

AF:

0.00202

Gnomad EAS exome

AF:

0.000853

Gnomad FIN exome

AF:

0.00188

Gnomad NFE exome

AF:

0.00452

Gnomad OTH exome

AF:

0.00331

GnomAD4 exome

AF:

0.00322

AC:

3116

AN:

967390

Hom.:

Cov.:

AF XY:

0.00308

AC XY:

1525

AN XY:

495440

show subpopulations

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

African (AFR)

AF:

0.00360

AC:

AN:

22208

American (AMR)

AF:

0.00394

AC:

128

AN:

32520

Ashkenazi Jewish (ASJ)

AF:

0.000807

AC:

AN:

21054

East Asian (EAS)

AF:

0.000413

AC:

AN:

33926

South Asian (SAS)

AF:

0.00147

AC:

AN:

66592

European-Finnish (FIN)

AF:

0.00148

AC:

AN:

48696

Middle Eastern (MID)

AF:

0.000649

AC:

AN:

4620

European-Non Finnish (NFE)

AF:

0.00374

AC:

2598

AN:

694826

Other (OTH)

AF:

0.00247

AC:

106

AN:

42948

⚠️ 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: 0.289

Heterozygous variant carriers

243

485

728

970

1213

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

200

300

400

500

<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:

0.000188

AC:

AN:

133270

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

63804

show subpopulations

African (AFR)

AF:

0.000114

AC:

AN:

34978

American (AMR)

AF:

0.000152

AC:

AN:

13176

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3224

East Asian (EAS)

AF:

0.00

AC:

AN:

4710

South Asian (SAS)

AF:

0.00

AC:

AN:

4226

European-Finnish (FIN)

AF:

0.000137

AC:

AN:

7274

Middle Eastern (MID)

AF:

0.00

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.000287

AC:

AN:

62696

Other (OTH)

AF:

0.00

AC:

AN:

1862

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

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:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Breast and/or ovarian cancer (1)

Hereditary cancer-predisposing syndrome (1)

Lynch syndrome (1)

Lynch syndrome 4;C5436817:Mismatch repair cancer syndrome 4 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.19

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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