chr7-5987154-C-CTCCTGAGAGTCCACATGT
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM4
The NM_000535.7(PMS2):c.1593_1610dupACATGTGGACTCTCAGGA(p.Glu537_Lys538insHisValAspSerGlnGlu) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
PMS2
NM_000535.7 disruptive_inframe_insertion
NM_000535.7 disruptive_inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.66
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 Uncertain_significance. Variant got 2 ACMG points.
PM4
Nonframeshift variant in NON repetitive region in NM_000535.7.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152198Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
1
AN:
152198
Hom.:
Cov.:
32
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:
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000821 AC: 12AN: 1461648Hom.: 0 Cov.: 42 AF XY: 0.00000963 AC XY: 7AN XY: 727158
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
12
AN:
1461648
Hom.:
Cov.:
42
AF XY:
AC XY:
7
AN XY:
727158
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 0.00000657 AC: 1AN: 152198Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74356
GnomAD4 genome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
1
AN:
152198
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
74356
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Bravo
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Lynch syndrome Uncertain:4
| Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jul 29, 2024 | This variant causes an in-frame duplication of six amino acids of the PMS2 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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 | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Oct 22, 2020 | The PMS2 c.1593_1610dupACATGTGGACTCTCAGGA (p.His532_Glu537dup) frameshift variant is absent in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/). This change inserts 6 amino acids (HVDSQE) into the PMS2 protein in a nonrepeat region; however, this insertion is not located within any functionally conserved domain of the PMS2 protein (PMID: 17230503) and the duplicated residues are not well conserved throughout evolution (BP3). To our knowledge, functional studies have not been performed and this variant has not been reported in individuals with Lynch syndrome or CMMRD. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting, BP3. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 01, 2015 | This sequence change inserts 18 nucleotides in exon 11 of the PMS2 mRNA (c.1593_1610dup). This leads to the insertion of 6 amino acid residues in the PMS2 protein (p.His532_Glu537dup) but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature. However, ClinVar contains an entry for this variant (Variation ID: 127764). This insertion change is not located within any functionally conserved domain of the PMS2 protein (PMID: 17230503) and the duplicated residues are not well conserved throughout evolution. In summary, this variant causes amino acid residues insertion into a region that does not contain known functional domains. Although there is no evidence to suggest that this change affects protein function or causes disease, the evidence available at this time is insufficient to prove that conclusively. For these reasons, this change has been classified as a Variant of Uncertain Significance. - |
Hereditary cancer-predisposing syndrome Uncertain:3
| Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 10, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 22, 2023 | The c.1593_1610dup18 variant (also known as p.H532_E537dup), located in coding exon 11 of the PMS2 gene, results from an in-frame duplication of 18 nucleotides at nucleotide positions 1593 to 1610. This results in the insertion of 6 extra residues (HVDSQE) between codons 532 and 537. This amino acid region is not well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 08, 2023 | This variant causes an in-frame duplication of six amino acids of the PMS2 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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. - |
PMS2-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 10, 2024 | The PMS2 c.1593_1610dup18 variant is predicted to result in an in-frame duplication (p.His532_Glu537dup). This variant was reported in individuals with head and neck squamous cell carcinoma and breast cancer (Cury et al. 2021. PubMed ID: 34598035; Guindalini et al. 2022. PubMed ID: 35264596). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as variant of uncertain significance in Clinvar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127764/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 01, 2023 | This variant, c.1593_1610dup, results in the insertion of 6 amino acid(s) of the PMS2 protein (p.His532_Glu537dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 127764). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Lynch syndrome 4 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 01, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at