7-5987311-G-T

Position:

chr7-5987311-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000535.7(PMS2):c.1454C>A(p.Thr485Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.057 in 1,614,064 control chromosomes in the GnomAD database, including 5,854 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. T485M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.052 ( 535 hom., cov: 31)

Exomes 𝑓: 0.057 ( 5319 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:21O:1

Conservation

PhyloP100: 0.0320

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=0.004676789).

BP6

Variant 7-5987311-G-T is Benign according to our data. Variant chr7-5987311-G-T is described in ClinVar as [Benign]. Clinvar id is 41702.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-5987311-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.332 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7 linkuse as main transcript	c.1454C>A	p.Thr485Lys	missense_variant	11/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12 linkuse as main transcript	c.1454C>A	p.Thr485Lys	missense_variant	11/15	1	NM_000535.7	P3	P54278-1

Frequencies

GnomAD3 genomes

AF:

0.0520

AC:

7903

AN:

152096

Hom.:

534

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0181

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0325

Gnomad ASJ

AF:

0.0628

Gnomad EAS

AF:

0.346

Gnomad SAS

AF:

0.159

Gnomad FIN

AF:

0.0877

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.0416

Gnomad OTH

AF:

0.0465

GnomAD3 exomes

AF:

0.0801

AC:

20146

AN:

251466

Hom.:

1895

AF XY:

0.0843

AC XY:

11455

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.0165

Gnomad AMR exome

AF:

0.0239

Gnomad ASJ exome

AF:

0.0624

Gnomad EAS exome

AF:

0.359

Gnomad SAS exome

AF:

0.153

Gnomad FIN exome

AF:

0.0890

Gnomad NFE exome

AF:

0.0423

Gnomad OTH exome

AF:

0.0676

GnomAD4 exome

AF:

0.0575

AC:

84022

AN:

1461850

Hom.:

5319

Cov.:

AF XY:

0.0603

AC XY:

43855

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.0170

Gnomad4 AMR exome

AF:

0.0235

Gnomad4 ASJ exome

AF:

0.0651

Gnomad4 EAS exome

AF:

0.370

Gnomad4 SAS exome

AF:

0.148

Gnomad4 FIN exome

AF:

0.0891

Gnomad4 NFE exome

AF:

0.0397

Gnomad4 OTH exome

AF:

0.0691

GnomAD4 genome

AF:

0.0520

AC:

7908

AN:

152214

Hom.:

535

Cov.:

AF XY:

0.0563

AC XY:

4188

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.0180

Gnomad4 AMR

AF:

0.0324

Gnomad4 ASJ

AF:

0.0628

Gnomad4 EAS

AF:

0.345

Gnomad4 SAS

AF:

0.159

Gnomad4 FIN

AF:

0.0877

Gnomad4 NFE

AF:

0.0416

Gnomad4 OTH

AF:

0.0521

Alfa

AF:

0.0361

Hom.:

Bravo

AF:

0.0445

TwinsUK

AF:

0.0367

AC:

136

ALSPAC

AF:

0.0361

AC:

139

ESP6500AA

AF:

0.0195

AC:

ESP6500EA

AF:

0.0407

AC:

350

ExAC

AF:

0.0801

AC:

9722

Asia WGS

AF:

0.251

AC:

870

AN:

3478

EpiCase

AF:

0.0407

EpiControl

AF:

0.0414

ClinVar

Significance: Benign

Submissions summary: Benign:21Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:6Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 20, 2017	p.Thr485Lys in exon 11 of PMS2: This variant is not expected to have clinical si gnificance because it has been identified in 35% (3077/8632) of East Asian chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs1805323). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 21, 2018	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Lynch syndrome 4

Benign:5

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Jul 07, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 11, 2023	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. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:3

Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 21, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 28932927, 28347324, 24728327) -

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 04, 2014	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 30, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 31, 2014	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

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	MAF >1% -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Endometrial carcinoma

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

PMS2, EXON11, c.1454C>A, p. Thr485Lys, Benign (ACMG 5) The c.1454C>A variant was identified in 7 of 338 chromosomes (frequency: 0.021) from individuals or families with HNPCC and Lynch Syndrome exhibiting cafâˆšÂ©-au-lait spots and cancer. (14756672_Thompson_2004, 15256438_Nakagawa_2004, 16472587_Hendriks_2006, 16619239_Clenndening_2006, 17993636_Gururangan_2008, 24027009_Drost_2013) The variant was also identified in dbSNP (ID: rs1805323 ) â€šÃ„ÃºWith benign alleleâ€šÃ„Ã¹, with a minor allele frequency of 0.112(1000 Genomes Project) HGMD, COSMIC, â€šÃ„ÃºMismatch Repair Genes Variant Databaseâ€šÃ„Ã¹, â€šÃ„ÃºInSiGHT Colon Cancer Databaseâ€šÃ„Ã¹, ClinVar database as a benign variant by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports). 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 247 of 2178 chromosomes (frequency: 0.113), and in Exome Variant Server project in 350 of 8600 (frequency: 0.041) European American and in 86 of 4406 (frequency: 0.019) African American alleles, increasing the likelihood that this is/may be a low frequency benign variant in certain populations of origin. This variant was identified in the Exome Aggregation Consortium database to have an allele frequency of 0.079. The p.Thr485Lys variant is not expected to have clinical significance because it is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Thr485 residue is not conserved in mammals and the variant amino acid Threonine (Thr) is present in Macaques, increasing the likelihood that this variant does not have clinical significance. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.0080

DANN

Benign

0.20

DEOGEN2

Benign

0.050

T;.;.;.;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.35

T;T;.;T;.

MetaRNN

Benign

0.0047

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

N;.;.;.;.

MutationTaster

Benign

1.0

P;P;P;P;P

PrimateAI

Benign

0.23

PROVEAN

Benign

0.46

N;N;.;.;.

REVEL

Benign

0.10

Sift

Benign

0.93

T;T;.;.;.

Sift4G

Benign

0.91

T;T;.;.;.

Polyphen

0.0

B;B;.;.;B

Vest4

0.034

MPC

0.042

ClinPred

0.0026

GERP RS

-10

Varity_R

0.046

gMVP

0.21

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

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