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

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 19, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2013	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. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Mar 04, 2025	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 13, 2016	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

Hereditary cancer-predisposing syndrome

Benign:7

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 26, 2014	- -
Benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Jan 15, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jul 12, 2017	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 28, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 03, 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. -
Benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Feb 03, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -

not provided

Benign:6Other:1

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 29, 2016	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -
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 10, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2025	PMS2: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 16, 2017	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. -

Lynch syndrome 4

Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Feb 05, 2016	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	May 08, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Lynch syndrome 1

Benign:2

Benign, no assertion criteria provided	clinical testing	Pathway Genomics	Oct 17, 2014	- -
Likely benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Oct 10, 2014	MAF >1% in a specific ethnic group (European American) -

Mismatch repair cancer syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jun 03, 2019

- -

Lynch syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Dec 22, 2015

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 04, 2025

- -

Endometrial carcinoma

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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

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