7-5987389-G-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000535.7(PMS2):āc.1376C>Gā(p.Ser459Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (ā ā ). Synonymous variant affecting the same amino acid position (i.e. S459S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000535.7 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PMS2 | NM_000535.7 | c.1376C>G | p.Ser459Ter | stop_gained | 11/15 | ENST00000265849.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PMS2 | ENST00000265849.12 | c.1376C>G | p.Ser459Ter | stop_gained | 11/15 | 1 | NM_000535.7 | P3 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461890Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 727246
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 15, 2020 | This variant changes 1 nucleotide in exon 11 of the PMS2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 07, 2018 | The p.S459* pathogenic mutation (also known as c.1376C>G), located in coding exon 11 of the PMS2 gene, results from a C to G substitution at nucleotide position 1376. This changes the amino acid from a serine to a stop codon within coding exon 11. The p.S459* alteration was identified in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med., 2016 08;18:823-32). This alteration was also reported as homozygous in a pediatric patient with acute lymphoblastic leukemia (ALL) and constitutional mismatch repair deficiency (CMMRD) was implicated (Oberg JA et al. Genome Med, 2016 12;8:133). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Lynch syndrome 4 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Sep 20, 2023 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
Pathogenic, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Feb 19, 2024 | This sequence change creates a premature translational stop signal (p.Ser459*) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). This variant is not present in population databases (ExAC no frequency). This premature translational stop signal has been observed in individual(s) with T-cell lymphoblastic lymphoma (PMID: 28007021). ClinVar contains an entry for this variant (Variation ID: 393103). For these reasons, this variant has been classified as Pathogenic. Heterozygous pathogenic/likely pathogenic variants in the PMS2 cause hereditary non-polyposis colorectal cancer syndrome, also known as Lynch Syndrome. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 29, 2019 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in the homozygous state in one individual with a hematologic malignancy in childhood (Oberg 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 28007021, 25883011, 31130284, 32359129) - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 03, 2020 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). This variant has been reported as homozygous in an individual affected with T-cell lymphoblastic lymphoma (PMID: 28007021). ClinVar contains an entry for this variant (Variation ID: 393103). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser459*) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. - |
Mismatch repair cancer syndrome 1 Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Sep 26, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at