chr7-5982995-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000535.7(PMS2):c.2007-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 1,449,408 control chromosomes in the GnomAD database, including 14,424 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.13 ( 1460 hom., cov: 30)

Exomes 𝑓: 0.14 ( 12964 hom. )

Consequence

PMS2
NM_000535.7 splice_region, intron

Scores

Splicing: ADA: 0.00005852

Clinical Significance

Benign reviewed by expert panel B:22

Conservation

PhyloP100: -0.223

Publications

17 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 7-5982995-C-T is Benign according to our data. Variant chr7-5982995-C-T is described in ClinVar as Benign. ClinVar VariationId is 91327.Status of the report is reviewed_by_expert_panel, 3 stars.

BA1

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

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.2007-4G>A	splice_region intron	N/A	NP_000526.2	P54278-1
PMS2	NM_001406866.1		c.2193-4G>A	splice_region intron	N/A	NP_001393795.1	A0A8V8TNX6
PMS2	NM_001322014.2		c.2007-4G>A	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.2007-4G>A	splice_region intron	N/A	ENSP00000265849.7	P54278-1
PMS2	ENST00000382321.5	TSL:1	c.804-4G>A	splice_region intron	N/A	ENSP00000371758.4	P54278-2
PMS2	ENST00000406569.8	TSL:1	n.1678+4092G>A	intron	N/A	ENSP00000514464.1	P54278-3

Frequencies

GnomAD3 genomes

AF:

0.129

AC:

19434

AN:

150994

Hom.:

1457

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0418

Gnomad AMI

AF:

0.183

Gnomad AMR

AF:

0.184

Gnomad ASJ

AF:

0.144

Gnomad EAS

AF:

0.297

Gnomad SAS

AF:

0.178

Gnomad FIN

AF:

0.125

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.151

Gnomad OTH

AF:

0.143

GnomAD2 exomes

AF:

0.161

AC:

24903

AN:

154878

AF XY:

0.160

show subpopulations

Gnomad AFR exome

AF:

0.0369

Gnomad AMR exome

AF:

0.223

Gnomad ASJ exome

AF:

0.148

Gnomad EAS exome

AF:

0.286

Gnomad FIN exome

AF:

0.123

Gnomad NFE exome

AF:

0.141

Gnomad OTH exome

AF:

0.151

GnomAD4 exome

AF:

0.144

AC:

186768

AN:

1298298

Hom.:

12964

Cov.:

AF XY:

0.146

AC XY:

94526

AN XY:

646644

show subpopulations

African (AFR)

AF:

0.0330

AC:

954

AN:

28874

American (AMR)

AF:

0.220

AC:

7890

AN:

35936

Ashkenazi Jewish (ASJ)

AF:

0.151

AC:

3704

AN:

24510

East Asian (EAS)

AF:

0.304

AC:

10923

AN:

35950

South Asian (SAS)

AF:

0.174

AC:

13533

AN:

77812

European-Finnish (FIN)

AF:

0.124

AC:

6241

AN:

50154

Middle Eastern (MID)

AF:

0.143

AC:

578

AN:

4048

European-Non Finnish (NFE)

AF:

0.137

AC:

135398

AN:

986738

Other (OTH)

AF:

0.139

AC:

7547

AN:

54276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

6729

13458

20187

26916

33645

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4784

9568

14352

19136

23920

<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:

0.129

AC:

19440

AN:

151110

Hom.:

1460

Cov.:

AF XY:

0.131

AC XY:

9658

AN XY:

73804

show subpopulations

African (AFR)

AF:

0.0418

AC:

1712

AN:

40972

American (AMR)

AF:

0.184

AC:

2789

AN:

15168

Ashkenazi Jewish (ASJ)

AF:

0.144

AC:

499

AN:

3460

East Asian (EAS)

AF:

0.297

AC:

1517

AN:

5102

South Asian (SAS)

AF:

0.177

AC:

848

AN:

4778

European-Finnish (FIN)

AF:

0.125

AC:

1311

AN:

10498

Middle Eastern (MID)

AF:

0.119

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.151

AC:

10264

AN:

67836

Other (OTH)

AF:

0.143

AC:

300

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

824

1648

2473

3297

4121

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

224

448

672

896

1120

<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:

0.128

Hom.:

536

Bravo

AF:

0.132

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

Lynch syndrome 4 (6)

Hereditary cancer-predisposing syndrome (2)

Lynch syndrome (2)

not provided (2)

Endometrial carcinoma (1)

Hereditary nonpolyposis colorectal neoplasms (1)

Lynch syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

6.6

(source)

DANN

Benign

0.69

PhyloP100

-0.22

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000059

dbscSNV1_RF

Benign

0.0060

SpliceAI score (max)

0.020

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