7-5987144-T-C

Position:

chr7-5987144-T-C

Variant summary

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

The NM_000535.7(PMS2):c.1621A>G(p.Lys541Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.85 in 1,611,014 control chromosomes in the GnomAD database, including 584,176 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. K541R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.87 ( 57167 hom., cov: 32)

Exomes 𝑓: 0.85 ( 527009 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15O:1

Conservation

PhyloP100: 1.50

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=1.4039015E-6).

BP6

Variant 7-5987144-T-C is Benign according to our data. Variant chr7-5987144-T-C is described in ClinVar as [Benign]. Clinvar id is 135065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5987144-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.917 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.1621A>G	p.Lys541Glu	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.1621A>G	p.Lys541Glu	missense_variant	11/15	1	NM_000535.7	P3	P54278-1

Frequencies

GnomAD3 genomes

AF:

0.865

AC:

131537

AN:

151998

Hom.:

57124

Cov.:

show subpopulations

Gnomad AFR

AF:

0.925

Gnomad AMI

AF:

0.938

Gnomad AMR

AF:

0.772

Gnomad ASJ

AF:

0.893

Gnomad EAS

AF:

0.915

Gnomad SAS

AF:

0.895

Gnomad FIN

AF:

0.843

Gnomad MID

AF:

0.899

Gnomad NFE

AF:

0.845

Gnomad OTH

AF:

0.855

GnomAD3 exomes

AF:

0.841

AC:

210907

AN:

250846

Hom.:

89510

AF XY:

0.848

AC XY:

115081

AN XY:

135714

show subpopulations

Gnomad AFR exome

AF:

0.925

Gnomad AMR exome

AF:

0.669

Gnomad ASJ exome

AF:

0.889

Gnomad EAS exome

AF:

0.921

Gnomad SAS exome

AF:

0.895

Gnomad FIN exome

AF:

0.839

Gnomad NFE exome

AF:

0.850

Gnomad OTH exome

AF:

0.840

GnomAD4 exome

AF:

0.849

AC:

1238139

AN:

1458898

Hom.:

527009

Cov.:

AF XY:

0.851

AC XY:

617868

AN XY:

725902

show subpopulations

Gnomad4 AFR exome

AF:

0.930

Gnomad4 AMR exome

AF:

0.681

Gnomad4 ASJ exome

AF:

0.887

Gnomad4 EAS exome

AF:

0.930

Gnomad4 SAS exome

AF:

0.893

Gnomad4 FIN exome

AF:

0.842

Gnomad4 NFE exome

AF:

0.845

Gnomad4 OTH exome

AF:

0.861

GnomAD4 genome

AF:

0.865

AC:

131629

AN:

152116

Hom.:

57167

Cov.:

AF XY:

0.864

AC XY:

64262

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.925

Gnomad4 AMR

AF:

0.771

Gnomad4 ASJ

AF:

0.893

Gnomad4 EAS

AF:

0.914

Gnomad4 SAS

AF:

0.895

Gnomad4 FIN

AF:

0.843

Gnomad4 NFE

AF:

0.845

Gnomad4 OTH

AF:

0.857

Alfa

AF:

0.854

Hom.:

73695

Bravo

AF:

0.859

TwinsUK

AF:

0.847

AC:

3141

ALSPAC

AF:

0.834

AC:

3216

ESP6500AA

AF:

0.918

AC:

4045

ESP6500EA

AF:

0.846

AC:

7270

ExAC

AF:

0.851

AC:

103334

Asia WGS

AF:

0.891

AC:

3101

AN:

3478

EpiCase

AF:

0.851

EpiControl

AF:

0.850

ClinVar

Significance: Benign

Submissions summary: Benign:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9Other:1

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 05, 2018	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 11, 2016	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Disclaimer: This variant has not undergone full assessment. The following are pr eliminary notes: Frequency -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Lynch syndrome 4

Benign:3

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	IntelligeneCG	Aug 18, 2017	- -

Mismatch repair cancer syndrome 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Lynch syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.50

CADD

Benign

5.5

DANN

Benign

0.22

DEOGEN2

Benign

0.052

T;.;.;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.00058

LIST_S2

Benign

0.22

T;T;.;T;.

MetaRNN

Benign

0.0000014

T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-1.9

N;.;.;.;.

MutationTaster

Benign

1.0

P;P;P;P;P

PrimateAI

Benign

0.25

PROVEAN

Benign

0.76

N;N;.;.;.

REVEL

Benign

0.16

Sift

Benign

1.0

T;T;.;.;.

Sift4G

Benign

1.0

T;T;.;.;.

Polyphen

0.0

B;B;.;.;B

Vest4

0.049

MPC

0.045

ClinPred

0.0016

GERP RS

4.7

Varity_R

0.044

gMVP

0.15

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