NM_000535.7:c.*17G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_000535.7(PMS2):c.*17G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.00046 ( 0 hom., cov: 19)

Exomes 𝑓: 0.00055 ( 95 hom. )

Failed GnomAD Quality Control

Consequence

PMS2
NM_000535.7 3_prime_UTR

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:12

Conservation

PhyloP100: -0.371

Publications

3 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 7-5973382-C-G is Benign according to our data. Variant chr7-5973382-C-G is described in ClinVar as Benign. ClinVar VariationId is 91277.Status of the report is reviewed_by_expert_panel, 3 stars.

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.*17G>C	3_prime_UTR	Exon 15 of 15	NP_000526.2	P54278-1
PMS2	NM_001406866.1		c.*17G>C	3_prime_UTR	Exon 16 of 16	NP_001393795.1	A0A8V8TNX6
PMS2	NM_001322014.2		c.*17G>C	3_prime_UTR	Exon 15 of 15	NP_001308943.1	A0A8V8TQ50

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PMS2	ENST00000265849.12	TSL:1 MANE Select	c.*17G>C	3_prime_UTR	Exon 15 of 15	ENSP00000265849.7	P54278-1
PMS2	ENST00000406569.8	TSL:1	n.*247G>C	non_coding_transcript_exon	Exon 13 of 13	ENSP00000514464.1	P54278-3
PMS2	ENST00000406569.8	TSL:1	n.*247G>C	3_prime_UTR	Exon 13 of 13	ENSP00000514464.1	P54278-3

Frequencies

GnomAD3 genomes

AF:

0.000458

AC:

AN:

122252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000308

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000514

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000975

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000702

Gnomad OTH

AF:

0.000620

GnomAD2 exomes

AF:

0.0000385

AC:

AN:

181594

AF XY:

0.0000305

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000201

Gnomad ASJ exome

AF:

0.000122

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000127

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000553

AC:

394

AN:

712486

Hom.:

Cov.:

AF XY:

0.000525

AC XY:

197

AN XY:

375338

show subpopulations

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

African (AFR)

AF:

0.000107

AC:

AN:

18734

American (AMR)

AF:

0.000422

AC:

AN:

33172

Ashkenazi Jewish (ASJ)

AF:

0.000154

AC:

AN:

19454

East Asian (EAS)

AF:

0.00

AC:

AN:

30864

South Asian (SAS)

AF:

0.0000961

AC:

AN:

62424

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

45932

Middle Eastern (MID)

AF:

0.000337

AC:

AN:

2970

European-Non Finnish (NFE)

AF:

0.000721

AC:

335

AN:

464640

Other (OTH)

AF:

0.000583

AC:

AN:

34296

⚠️ 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: 0.273

Heterozygous variant carriers

124

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000458

AC:

AN:

122320

Hom.:

Cov.:

AF XY:

0.000408

AC XY:

AN XY:

58782

show subpopulations

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

African (AFR)

AF:

0.0000308

AC:

AN:

32514

American (AMR)

AF:

0.000514

AC:

AN:

11668

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3002

East Asian (EAS)

AF:

0.00

AC:

AN:

3846

South Asian (SAS)

AF:

0.00

AC:

AN:

3470

European-Finnish (FIN)

AF:

0.000975

AC:

AN:

8208

Middle Eastern (MID)

AF:

0.00

AC:

AN:

252

European-Non Finnish (NFE)

AF:

0.000703

AC:

AN:

56936

Other (OTH)

AF:

0.000613

AC:

AN:

1632

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.276

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:

0.00218

Hom.:

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Lynch syndrome (3)

Lynch syndrome 4 (3)

Breast and/or ovarian cancer (1)

Hereditary cancer-predisposing syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

1.3

(source)

DANN

Benign

0.59

PhyloP100

-0.37

Mutation Taster

=100/0

polymorphism

(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

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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