7-5987246-T-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_000535.7(PMS2):c.1519A>G(p.Ser507Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. S507N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 0.420

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: ClinGen, Orphanet
Lynch syndrome 4
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
mismatch repair cancer syndrome 1
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
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: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08329055).

BP6

Variant 7-5987246-T-C is Benign according to our data. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340. Variant chr7-5987246-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 186340.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7 link	c.1519A>G	p.Ser507Gly	missense_variant	Exon 11 of 15	ENST00000265849.12	NP_000526.2	P54278-1Q7Z3Q2B4DGM0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12 link	c.1519A>G	p.Ser507Gly	missense_variant	Exon 11 of 15	1	NM_000535.7	ENSP00000265849.7		P54278-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000137

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111996

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Benign:2

May 24, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Jan 21, 2025

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lynch syndrome

Uncertain:1

Apr 03, 2023

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces serine with glycine at codon 507 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Nov 15, 2019

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Hereditary nonpolyposis colorectal neoplasms

Uncertain:1

Oct 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 507 of the PMS2 protein (p.Ser507Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 186340). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt PMS2 function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.11

T;.;.;.;.

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.56

T;T;.;T;.

M_CAP

Benign

0.022

MetaRNN

Benign

0.083

T;T;T;T;T

MetaSVM

Benign

-0.70

MutationAssessor

Benign

1.4

L;.;.;.;.

PhyloP100

0.42

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.2

N;N;.;.;.

REVEL

Benign

0.13

Sift

Benign

0.24

T;T;.;.;.

Sift4G

Benign

0.17

T;T;.;.;.

Polyphen

0.0020

B;B;.;.;B

Vest4

0.096

MutPred

0.26

Loss of phosphorylation at S507 (P = 0.01);.;.;.;.;

MVP

0.41

MPC

0.035

ClinPred

0.032

GERP RS

-0.79

Varity_R

0.032

gMVP

0.19

Mutation Taster

=90/10

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over