7-5982849-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_000535.7(PMS2):c.2149G>A(p.Val717Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00067 in 1,608,702 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V717L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00071 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00067 ( 1 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:20

Conservation

PhyloP100: 1.07

Publications

19 publications found

Variant links:

COSMIC-nc: COSV56221991

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02527678).

BP6

Variant 7-5982849-C-T is Benign according to our data. Variant chr7-5982849-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 41709.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000705 (107/151750) while in subpopulation AMR AF = 0.00177 (27/15240). AF 95% confidence interval is 0.00125. There are 1 homozygotes in GnomAd4. There are 48 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

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	HGVSp	Effect	Exon Rank	Protein	UniProt
PMS2	NM_000535.7	MANE Select	c.2149G>A	p.Val717Met	missense	Exon 12 of 15	NP_000526.2	P54278-1
PMS2	NM_001406866.1		c.2335G>A	p.Val779Met	missense	Exon 13 of 16	NP_001393795.1	A0A8V8TNX6
PMS2	NM_001322014.2		c.2149G>A	p.Val717Met	missense	Exon 12 of 15	NP_001308943.1	A0A8V8TQ50

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PMS2	ENST00000265849.12	TSL:1 MANE Select	c.2149G>A	p.Val717Met	missense	Exon 12 of 15	ENSP00000265849.7	P54278-1
PMS2	ENST00000382321.5	TSL:1	c.946G>A	p.Val316Met	missense	Exon 8 of 11	ENSP00000371758.4	P54278-2
PMS2	ENST00000406569.8	TSL:1	n.1678+4238G>A		intron	N/A	ENSP00000514464.1	P54278-3

Frequencies

GnomAD3 genomes

AF:

0.000706

AC:

107

AN:

151632

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000974

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00722

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000735

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.000758

AC:

180

AN:

237492

AF XY:

0.000759

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000758

Gnomad ASJ exome

AF:

0.00699

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000480

Gnomad NFE exome

AF:

0.000731

Gnomad OTH exome

AF:

0.00136

GnomAD4 exome

AF:

0.000666

AC:

971

AN:

1456952

Hom.:

Cov.:

AF XY:

0.000682

AC XY:

494

AN XY:

724746

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

33184

American (AMR)

AF:

0.000878

AC:

AN:

44440

Ashkenazi Jewish (ASJ)

AF:

0.00783

AC:

204

AN:

26062

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.0000233

AC:

AN:

85876

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4160

European-Non Finnish (NFE)

AF:

0.000584

AC:

648

AN:

1110040

Other (OTH)

AF:

0.00118

AC:

AN:

60136

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

100

151

201

251

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

104

130

<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:

0.000705

AC:

107

AN:

151750

Hom.:

Cov.:

AF XY:

0.000647

AC XY:

AN XY:

74190

show subpopulations

African (AFR)

AF:

0.0000971

AC:

AN:

41210

American (AMR)

AF:

0.00177

AC:

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.00722

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000735

AC:

AN:

67982

Other (OTH)

AF:

0.000475

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

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:

0.00137

Hom.:

Bravo

AF:

0.000782

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000234

AC:

ExAC

AF:

0.000635

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (7)

not specified (7)

Lynch syndrome (4)

Lynch syndrome 4 (3)

not provided (3)

Breast and/or ovarian cancer (1)

Hereditary cancer (1)

Hereditary nonpolyposis colorectal neoplasms (1)

Lynch syndrome 4;C5399763:Mismatch repair cancer syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.86

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.025

MetaSVM

Uncertain

0.42

MutationAssessor

Uncertain

2.8

PhyloP100

1.1

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.8

REVEL

Uncertain

0.36

Sift

Uncertain

0.010

Sift4G

Uncertain

0.054

Polyphen

0.98

Vest4

0.49

MVP

0.78

MPC

2.2

ClinPred

0.087

GERP RS

3.8

Varity_R

0.28

gMVP

0.35

Mutation Taster

=70/30

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