chr7-5982986-G-A
Position:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_000535.7(PMS2):c.2012C>T(p.Thr671Met) variant causes a missense change. The variant allele was found at a frequency of 0.000228 in 1,515,790 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00018 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00023 ( 1 hom. )
Consequence
PMS2
NM_000535.7 missense
NM_000535.7 missense
Scores
10
9
Clinical Significance
Conservation
PhyloP100: 5.70
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 Likely_benign. Variant got -3 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.17239493).
BP6
Variant 7-5982986-G-A is Benign according to our data. Variant chr7-5982986-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127770.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=19, not_provided=1, Benign=2}. Variant chr7-5982986-G-A is described in Lovd as [Likely_benign].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PMS2 | NM_000535.7 | c.2012C>T | p.Thr671Met | missense_variant | 12/15 | ENST00000265849.12 | NP_000526.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PMS2 | ENST00000265849.12 | c.2012C>T | p.Thr671Met | missense_variant | 12/15 | 1 | NM_000535.7 | ENSP00000265849.7 |
Frequencies
GnomAD3 genomes 0.000178 AC: 27AN: 151324Hom.: 0 Cov.: 31
GnomAD3 genomes
AF:
AC:
27
AN:
151324
Hom.:
Cov.:
31
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000190 AC: 32AN: 168512Hom.: 0 AF XY: 0.000219 AC XY: 20AN XY: 91418
GnomAD3 exomes
AF:
AC:
32
AN:
168512
Hom.:
AF XY:
AC XY:
20
AN XY:
91418
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000234 AC: 319AN: 1364466Hom.: 1 Cov.: 22 AF XY: 0.000249 AC XY: 169AN XY: 678008
GnomAD4 exome
AF:
AC:
319
AN:
1364466
Hom.:
Cov.:
22
AF XY:
AC XY:
169
AN XY:
678008
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome 0.000178 AC: 27AN: 151324Hom.: 0 Cov.: 31 AF XY: 0.000149 AC XY: 11AN XY: 73844
GnomAD4 genome
AF:
AC:
27
AN:
151324
Hom.:
Cov.:
31
AF XY:
AC XY:
11
AN XY:
73844
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ExAC
AF:
AC:
21
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:21Benign:4Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:7
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 04, 2022 | BP4 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 17, 2024 | In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26483394, 31422574, 22229248, 27449771, 28135145, 29101607, 29785153, 25186627, 31159747, 30613976, 34271781, 33120919, 33939675, 26321251, 35372080, 35402282, 30113427, 35089076, 33471991, 37534630, 35263119, 34326862, 11292842) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PMS2 p.Thr671Met variant was identified in 3 of 260 proband chromosomes (frequency: 0.01) from individuals or families with breast cancer of Romanian ethnicity (Goidescu 2017). The variant was also identified in dbSNP (ID: rs587780046) as with uncertain significance allele; and in ClinVar and Clinvitae databases as benign by Ambry Genetics and uncertain significance by Invitae, Praxis fuer Humangenetik Tuebingen, Quest Diagnostics - Nichols Institute San Juan Capistrano, Fulgent Genetics, GeneDx and Pathway Genomics. The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database, databases. The variant was identified in control databases in 34 of 195042 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include other in 3 of 5030 chromosomes (freq: 0.0006), European Non-Finnish in 27 of 81252 chromosomes (freq: 0.0003), East Asian in 2 of 13498 chromosomes (freq: 0.0001), and South Asian in 2 of 23600 chromosomes (freq: 0.0001), while the variant was not observed in the African, Latino, Ashkenazi Jewish, European Finnish, populations. The p.Thr671 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Jan 29, 2024 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 27, 2023 | The PMS2 c.2012C>T (p.Thr671Met) variant has been reported in the published literature in affected individuals with pancreatic cancer (PMIDs: 26483394 (2015), 27449771 (2016)), breast cancer (PMIDs: 25186627 (2015), 29785153 (2018), 31159747 (2019), 31422574 (2019), 33120919 (2020), 35402282 (2022), 37534630 (2023)), and colorectal cancer/suspected Lynch syndrome (PMIDs: 28135145 (2017), 34271781 (2021), 35372080 (2022)). This variant has been reported in individuals with breast cancer as well as in unaffected controls in a breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PMS2)). The frequency of this variant in the general population, 0.00035 (29/83638 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Lynch syndrome 4 Uncertain:5
| Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Mar 17, 2022 | The PMS2 c.2012C>T (p.Thr671Met) missense change has a maximum subpopulation frequency of 0.035% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/7-6022617-G-A?dataset=gnomad_r2_1). This variant is located in exon 12 of the PMS2 gene and data in this region are not considered reliable due to high pseudogene homology. This variant was reported in 2 of 1,058 individuals with colorectal cancer (PMID: 28135145). One of the individuals also harbored a pathogenic germline variant in MUTYH (c.891+3A>C). The tumor of this individual was determined to be MMR proficient and microsatellite stable (PMID: 28135145). This variant has also been reported in individuals with breast cancer (PMID: 25186627, 29785153, 30613976) and pancreatic cancer (PMID: 26483394, 27449771). In silico tools are not in agreement about the effect of this variant on protein function, but to our knowledge these predictions have not been confirmed by functional assays. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: not criteria met. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Nov 12, 2019 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 20, 2023 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jul 18, 2022 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Hereditary cancer-predisposing syndrome Uncertain:4Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 02, 2023 | This missense variant replaces threonine with methionine at codon 671 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast/ovarian cancer (PMID: 25186627, 29785153, 31422574, 33120919), colorectal (PMID: 28135145), or pancreatic cancer (PMID: 2648339). This variant has been identified in 35/199754 chromosomes in the general population by the Genome Aggregation Database (gnomAD). However, this observed allele frequency is not considered reliable, because the gnomAD dataset does not disambiguate possible interference from homologous sequences in the PMS2CL pseudogene. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
| Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 11, 2015 | 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Oct 10, 2023 | - - |
| Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 22, 2022 | - - |
not specified Uncertain:2Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 09, 2021 | DNA sequence analysis of the PMS2 gene demonstrated a sequence change, c.2012C>T, in exon 12 that results in an amino acid change, p.Thr671Met. This sequence change has been described in gnomAD with a frequency of 0.035% in the Non-Finnish European sub-population (dbSNP rs587780046). The p.Thr671Met change affects a poorly conserved amino acid residue located in a domain of the PMS2 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Thr671Met substitution. The c.2012C>T sequence change has been reported in the literature in individuals affected with breast cancer, colorectal cancer or pancreatic cancer (PMIDs: 25186627, 26483394, 27449771, 28135145, 29785153, 30613976, 31159747) but has also been reported in individuals without a cancer diagnosis (PMID: 31422574). One of the reported colorectal cancer patients also carried a pathogenic variant in the KRAS gene (c.34G>T, p.Gly12Cys). The patient's tumor was determined to be MMR proficient and microsatellite stable (PMID: 28135145). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Thr671Met change remains unknown at this time. - |
| Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 23, 2024 | Variant summary: PMS2 c.2012C>T (p.Thr671Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 168512 control chromosomes. The observed variant frequency is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (7.1e-05). However, this PMS2 locus is highly homologous to PMS2 pseudogene and the technology utilized for these datasets does not rule out pseudogene interference, therefore these data might not be reliable. c.2012C>T has been reported in the literature in individuals affected with breast cancer, colorectal cancer, ovarian cancer or pancreatic cancer (e.g. Tung 2015, Hu 2016, Yang 2016, Yurgelun 2017, Goidescu 2018, Rizzolo_2019, Tsaousis_2019, Duzkale_2021, Sahin_2022, Abdel-Razeq_2022, Dorling_2021, Delahunty_2022,) but has also been reported in individual(s) without a cancer diagnosis (e.g. Kraemer_2019). One of the reported colorectal cancer patients had a co-occurring pathogenic variant (KRAS c.34G>T, p.Gly12Cys) while the patient's tumor was determined to be MMR proficient and microsatellite stable (Yurgelun_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35402282, 35263119, 33471991, 34271781, 29785153, 35372080, 26483394, 31422574, 30613976, 35089076, 31159747, 25186627, 27449771, 28135145, 33120919, 30113427). ClinVar contains an entry for this variant (Variation ID: 127770). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Breast and/or ovarian cancer Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Nov 04, 2022 | - - |
Lynch syndrome 4;C5399763:Mismatch repair cancer syndrome 1 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 23, 2017 | - - |
Lynch syndrome 1 Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Pathway Genomics | Jul 24, 2014 | - - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Hereditary breast ovarian cancer syndrome Benign:1
| Likely benign, criteria provided, single submitter | curation | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Sep 09, 2024 | According to the ClinGen InSiGHT ACMG PMS2 v1.0.0 criteria we chose these criteria: BP4 (supporting benign): REVEL : Score: 0.109, BS1 (strong benign): Grpmax Filtering AF (gAD v3) = 0.0002305 (>0.0001) - |
Lynch syndrome;C5436817:Mismatch repair cancer syndrome 4 Other:1
| not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Uncertain significance and reported on 07-28-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;.;D;.;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;.;.;.;.;.
PrimateAI
Benign
T
PROVEAN
Benign
N;N;.;.;.;N
REVEL
Benign
Sift
Uncertain
D;D;.;.;.;D
Sift4G
Uncertain
D;D;.;.;.;T
Polyphen
P;P;.;.;P;D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at