7-5987234-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000535.7(PMS2):c.1531A>G(p.Thr511Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0266 in 1,614,066 control chromosomes in the GnomAD database, including 678 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T511M) has been classified as Benign.

Frequency

Genomes: 𝑓 0.021 ( 53 hom., cov: 32)

Exomes 𝑓: 0.027 ( 625 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:26O:1

Conservation

PhyloP100: -0.352

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0029952526).

BP6

Variant 7-5987234-T-C is Benign according to our data. Variant chr7-5987234-T-C is described in ClinVar as [Benign]. Clinvar id is 41703.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-5987234-T-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0215 (3267/152240) while in subpopulation NFE AF= 0.0277 (1886/68026). AF 95% confidence interval is 0.0267. There are 53 homozygotes in gnomad4. There are 1694 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 53 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7 link	c.1531A>G	p.Thr511Ala	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.1531A>G	p.Thr511Ala	missense_variant	Exon 11 of 15	1	NM_000535.7	ENSP00000265849.7		P54278-1

Frequencies

GnomAD3 genomes

AF:

0.0215

AC:

3267

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00632

Gnomad AMI

AF:

0.0186

Gnomad AMR

AF:

0.0161

Gnomad ASJ

AF:

0.0381

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0207

Gnomad FIN

AF:

0.0538

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0277

Gnomad OTH

AF:

0.0230

GnomAD3 exomes

AF:

0.0246

AC:

6176

AN:

251328

Hom.:

105

AF XY:

0.0254

AC XY:

3446

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.00481

Gnomad AMR exome

AF:

0.0115

Gnomad ASJ exome

AF:

0.0315

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0200

Gnomad FIN exome

AF:

0.0544

Gnomad NFE exome

AF:

0.0302

Gnomad OTH exome

AF:

0.0261

GnomAD4 exome

AF:

0.0272

AC:

39709

AN:

1461826

Hom.:

625

Cov.:

AF XY:

0.0270

AC XY:

19627

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.00490

Gnomad4 AMR exome

AF:

0.0119

Gnomad4 ASJ exome

AF:

0.0315

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0208

Gnomad4 FIN exome

AF:

0.0516

Gnomad4 NFE exome

AF:

0.0288

Gnomad4 OTH exome

AF:

0.0248

GnomAD4 genome

AF:

0.0215

AC:

3267

AN:

152240

Hom.:

Cov.:

AF XY:

0.0228

AC XY:

1694

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.00631

Gnomad4 AMR

AF:

0.0161

Gnomad4 ASJ

AF:

0.0381

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0207

Gnomad4 FIN

AF:

0.0538

Gnomad4 NFE

AF:

0.0277

Gnomad4 OTH

AF:

0.0227

Alfa

AF:

0.0258

Hom.:

Bravo

AF:

0.0181

TwinsUK

AF:

0.0272

AC:

101

ALSPAC

AF:

0.0283

AC:

109

ESP6500AA

AF:

0.00635

AC:

ESP6500EA

AF:

0.0281

AC:

242

ExAC

AF:

0.0250

AC:

3041

EpiCase

AF:

0.0285

EpiControl

AF:

0.0268

ClinVar

Significance: Benign

Submissions summary: Benign:26Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:9Other:1

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 28, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 03, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Lynch syndrome 4

Benign:7

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Jul 07, 2017

Counsyl

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 11, 2023

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 22, 2015

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:4

Jan 02, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 2018

True Health Diagnostics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 21, 2015

Vantari Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 14, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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. -

Lynch syndrome

Benign:2

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: research

MAF >1% -

Sep 30, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Nov 06, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Endometrial carcinoma

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PMS2, EXON11, c.1531A>G, p.Thr511Ala, Benign (ACMG 5) The c.1531A>G variant was identified in 6 of 368 proband chromosomes (frequency: 0.016) from individuals or families with HNPCC and Lynch syndrome; however, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. The variant was present in individuals that tested immunohistocompatibility PMS2 negative but positive for MLH1, MSH2 and MSH 6. Tumours were also found to be microsatellite instability high. (10479499_Basil_1999, 15256438_Nakagawa, 16619239_Clenndening_2006, 24027009_Drost_2013) The variant was also identified in dbSNP (ID: rs2228007) â€šÃ„ÃºWith untested alleleâ€šÃ„Ã¹, with a minor allele frequency of 0.011 (1000 Genomes Project), â€šÃ„ÃºMismatch Repair Genes Variant Databaseâ€šÃ„Ã¹, â€šÃ„ÃºMMR Gene Unclassified Variants Databaseâ€šÃ„Ã¹, â€šÃ„ÃºInSiGHT Colon Cancer Databaseâ€šÃ„Ã¹, and ClinVar database as a benign variant.The variant was classified as a benign/likely benign variant by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports) with 6 separate submitters. The variant was classified as â€šÃ„Ãºunclassifiedâ€šÃ„Ã¹ by a clinical laboratory within the Canadian Open Genetics Repository (http://opengenetics.ca/). This variant was identified in the 1000 Genomes Project in 26 of 2178 chromosomes (frequency: 0.0119), Exome Variant Server project in 270 of 13006 European American/African American alleles (frequency: 0.02), increasing the likelihood that this is/may be a low frequency benign variant in certain populations of origin. The p.Thr511 residue is not conserved in mammals and the variant amino acid Threonine (Thr) is present in Macaques and Trichoplax adhaerens, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity but it increases the likelihood that this variant does not have clinical significance. The c.1531A>G variant occurs outside of the splicing consensus sequence and in silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) does not predict a difference in splicing in 5 of 5 different programs. (However, this information is not predictive enough to rule out pathogenicity.) In summary, based on the above information, the clinical significance of this variant satisfies our laboratory requirements as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.32

DANN

Benign

0.17

DEOGEN2

Benign

0.087

T;.;.;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.40

T;T;.;T;.

MetaRNN

Benign

0.0030

T;T;T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

0.76

N;.;.;.;.

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.75

N;N;.;.;.

REVEL

Benign

0.031

Sift

Benign

0.76

T;T;.;.;.

Sift4G

Benign

0.88

T;T;.;.;.

Polyphen

0.0

B;B;.;.;B

Vest4

0.017

MPC

0.036

ClinPred

0.0021

GERP RS

1.9

Varity_R

0.016

gMVP

0.18

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over