7-6006003-T-C

Variant names:

Variant summary

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

The NM_001406875.1(PMS2):c.-433A>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.011 in 1,610,660 control chromosomes in the GnomAD database, including 132 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).

Frequency

Genomes: 𝑓 0.0083 ( 9 hom., cov: 32)

Exomes 𝑓: 0.011 ( 123 hom. )

Consequence

PMS2
NM_001406875.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Likely benign reviewed by expert panel U:1B:32O:2

Conservation

PhyloP100: 5.91

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=0.009115964).

BP6

Variant 7-6006003-T-C is Benign according to our data. Variant chr7-6006003-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 41713.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-6006003-T-C is described in Lovd as [Benign]. Variant chr7-6006003-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00832 (1267/152298) while in subpopulation NFE AF= 0.0115 (780/68032). AF 95% confidence interval is 0.0108. There are 9 homozygotes in gnomad4. There are 621 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7 link	c.52A>G	p.Ile18Val	missense_variant	Exon 2 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.52A>G	p.Ile18Val	missense_variant	Exon 2 of 15	1	NM_000535.7	ENSP00000265849.7		P54278-1

Frequencies

GnomAD3 genomes

AF:

0.00831

AC:

1265

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00171

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00439

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.0301

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0115

Gnomad OTH

AF:

0.00670

GnomAD3 exomes

AF:

0.00901

AC:

2213

AN:

245572

Hom.:

AF XY:

0.00917

AC XY:

1229

AN XY:

134082

show subpopulations

Gnomad AFR exome

AF:

0.00213

Gnomad AMR exome

AF:

0.00180

Gnomad ASJ exome

AF:

0.000402

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00306

Gnomad FIN exome

AF:

0.0325

Gnomad NFE exome

AF:

0.0115

Gnomad OTH exome

AF:

0.00924

GnomAD4 exome

AF:

0.0112

AC:

16400

AN:

1458362

Hom.:

123

Cov.:

AF XY:

0.0111

AC XY:

8035

AN XY:

725510

show subpopulations

Gnomad4 AFR exome

AF:

0.00174

Gnomad4 AMR exome

AF:

0.00237

Gnomad4 ASJ exome

AF:

0.000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00370

Gnomad4 FIN exome

AF:

0.0324

Gnomad4 NFE exome

AF:

0.0122

Gnomad4 OTH exome

AF:

0.0107

GnomAD4 genome

AF:

0.00832

AC:

1267

AN:

152298

Hom.:

Cov.:

AF XY:

0.00834

AC XY:

621

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00171

Gnomad4 AMR

AF:

0.00439

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00311

Gnomad4 FIN

AF:

0.0301

Gnomad4 NFE

AF:

0.0115

Gnomad4 OTH

AF:

0.00663

Alfa

AF:

0.00582

Hom.:

Bravo

AF:

0.00652

TwinsUK

AF:

0.0124

AC:

ALSPAC

AF:

0.0140

AC:

ESP6500AA

AF:

0.00331

AC:

ESP6500EA

AF:

0.0113

AC:

ExAC

AF:

0.00899

AC:

1048

EpiCase

AF:

0.0104

EpiControl

AF:

0.0105

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:32Other:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:8Other:1

Dec 19, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 12, 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. -

Sep 13, 2016

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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: Likely benign

Review Status: no assertion criteria provided

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

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:7

Sep 03, 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. -

Aug 01, 2018

GeneKor MSA

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 28, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Feb 03, 2016

Vantari Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 26, 2014

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 15, 2018

True Health Diagnostics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 12, 2017

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:6Other:1

Nov 10, 2023

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

- -

Aug 16, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The PMS2 c.52A>G (p.Ile18Val) variant located in the Histidine kinase-like ATPase, C-terminal domain of the protein (via InterPro) involves the alteration of a conserved nucleotide and 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). However, a functional study indicates the variant does not affect MMR activity (Drost_2013. This variant was found in 2457/271244 control chromosomes (gnomAD) including 22 homozygotes at a frequency of 0.0090519, which is approximately 80 times the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136), suggesting this variant is likely a benign polymorphism. However, this observation needs to be cautiously considered because the sequencing technology (exome and genome sequencing) used cannot rule out the fact that the pseudogene could have been amplified. Several publications have cited the variant in affected individuals with Lynch Syndrome or related disorders, including reports of lack of cosegregation with disease in multiple families (Leongamornlert_2014 and Hendriks_2006). This variant also co-occurred with another pathogenic variant in a CRC patient and a suspected LS patient (Haraldsdottir_2017 and van der Klift_2016). In addition, in multiple internal LCA samples this variant was found to co-occur with another pathogenic or likely pathogenic variants such as PMS2 c.137G>T (p.Ser46Ile), MSH6 c.1634_1637delAAGA (p.Lys545fsX25), BRCA2 c.4647_4650delAGAG (p.Lys1549fsX18) MUTYH c.933+3A>C, MSH2 c.2038C>T (p.Arg680X) and PMS2 c.251-2A>T and MLH1 c.955G>T (p.Glu319X). Furthermore, multiple clinical diagnostic laboratories/reputable databases in ClinVar have classified this variant as likely benign/benign. Therefore due to the lack of cosegregation with disease, multiple co-occurrences with a pathogenic/likely pathogenic variant, and multiple clinical diagnostic laboratories classifying the variant as "likely benign/benign," the variant of interest has been classified as Benign. -

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 29, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PMS2: BS1, BS2 -

Lynch syndrome 4

Benign:6

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 08, 2015

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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. -

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 2016

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome 1

Benign:2

Oct 17, 2014

Pathway Genomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 10, 2014

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: research

MAF >1% in a specific ethnic group (European American) -

Mismatch repair cancer syndrome 1

Uncertain:1

Jun 03, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome

Benign:1

Dec 22, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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, EXON2, c.52A>G, p.Ile18Val, Heterozygous, Benign The PMS2 p.Ile18Val variant was identified in 11 of 1400 proband chromosomes (frequency: 0.008) from individuals or families with colorectal cancer, prostate cancer, or common variable immunodeficiency disorder and was present in 1 of 1552 control chromosomes (frequency: 0.0006) from healthy individuals (Clendenning 2006, Hendriks 2006, Van Schouwenburg 2015, van der Klift 2016, Leongamornlert 2014, Bodian 2014). The variant was also identified in dbSNP (ID: rs63750123) as "With other allele", and ClinVar (classified as benign by fifteen submitters; as likely benign by six submitters). The variant was identified in control databases in 2457 of 271244 chromosomes (22 homozygous) at a frequency of 0.009, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 44 of 22858 chromosomes (freq: 0.002), Other in 50 of 6380 chromosomes (freq: 0.008), Latino in 65 of 34296 chromosomes (freq: 0.002), European in 1387 of 122680 chromosomes (freq: 0.01), Ashkenazi Jewish in 5 of 9990 chromosomes (freq: 0.0005), Finnish in 811 of 25762 chromosomes (freq: 0.03), and South Asian in 95 of 30546 chromosomes (freq: 0.003); it was not observed in the East Asian population. The p.Ile18 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In addition, the variant demonstrated repair efficiency similar to wild type and repair-proficient controls (Drost 2013). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. Assessment Date: 2019/07/22 References (PMIDs): 16619239, 24027009, 16472587, 26122175, 27435373, 24556621, 24728327 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.049

BayesDel_noAF

Pathogenic

0.17

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.24

T;.

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

D;D

MetaRNN

Benign

0.0091

T;T

MetaSVM

Uncertain

0.69

MutationAssessor

Uncertain

2.9

M;M

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.89

N;N

REVEL

Uncertain

0.64

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.66

MVP

0.93

MPC

0.25

ClinPred

0.019

GERP RS

5.7

Varity_R

0.38

gMVP

0.40

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