7-6006003-T-C

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

6
5
7

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]

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
PMS2NM_000535.7 linkc.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
PMS2ENST00000265849.12 linkc.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.:
8
Cov.:
32
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.:
21
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.:
31
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.:
9
Cov.:
32
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.:
2
Bravo
AF:
0.00652
TwinsUK
AF:
0.0124
AC:
46
ALSPAC
AF:
0.0140
AC:
54
ESP6500AA
AF:
0.00331
AC:
9
ESP6500EA
AF:
0.0113
AC:
52
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
Sep 19, 2013
ITMI
Significance: not provided
Review Status: no classification provided
Collection Method: reference population

- -

Dec 19, 2016
PreventionGenetics, part of Exact Sciences
Significance: 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

- -

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

- -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Likely 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

- -

-
Mayo Clinic Laboratories, Mayo Clinic
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:7
Jan 15, 2018
True Health Diagnostics
Significance: Benign
Review Status: no assertion criteria provided
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

- -

Aug 01, 2018
GeneKor MSA
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 03, 2016
Vantari Genetics
Significance: 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

- -

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. -

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
Jul 13, 2012
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: research

- -

Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PMS2: BS1, BS2 -

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

- -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Likely benign
Review Status: no assertion criteria provided
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. -

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. -

Nov 10, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Lynch syndrome 4 Benign:6
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. -

Feb 05, 2016
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Likely benign
Review Status: criteria provided, single submitter
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

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jul 07, 2023
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 28, 2019
Mendelics
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
T
BayesDel_noAF
Pathogenic
0.17
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.24
T;.
Eigen
Pathogenic
0.75
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.91
D;D
MetaRNN
Benign
0.0091
T;T
MetaSVM
Uncertain
0.69
D
MutationAssessor
Uncertain
2.9
M;M
PrimateAI
Benign
0.44
T
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
T
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.

Other links and lift over

dbSNP: rs63750123; hg19: chr7-6045634; COSMIC: COSV56149828; COSMIC: COSV56149828; API