7-6009032-C-G
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong
The NM_000535.7(PMS2):c.-13G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )
Consequence
PMS2
NM_000535.7 5_prime_UTR
NM_000535.7 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: -2.12
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.68).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PMS2 | NM_000535.7 | c.-13G>C | 5_prime_UTR_variant | 1/15 | ENST00000265849.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PMS2 | ENST00000265849.12 | c.-13G>C | 5_prime_UTR_variant | 1/15 | 1 | NM_000535.7 | P3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249854Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135476
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1460084Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 726352
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Lynch syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 13, 2023 | This variant causes a G to C nucleotide substitution at the -13 position in the 5' untranslated region of the PMS2 gene. To our knowledge, functional studies have not been reported for this variant. Splice site prediction tools suggest that this variant may not impact RNA splicing. This variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has been identified in 3/249854 chromosomes 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. - |
Endometrial carcinoma Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.? (c.-13G>C) variant in exon 1 of the PMS2 gene has not been reported in the literature nor previously identified by our laboratory. This variant did not show up in the databases (dbSNP, NHLBI Exome sequencing project (exome variant server), HGMD, LOVD, COSMIC, UMD, ClinVar, or BIC) and it is unknown if it may or may not be causative of the disorder. It is unlikely that this will cause a missense mutation as it occurs outside of the translated sequence. This residue has not been seen in mammals and computational analyses (PolyPhen2, SIFT, AlignGVGD) and it is unknown if this suggests a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of this variant cannot be determined with certainty at this time; however based upon the arguments described above, we find this variant to be a VARIANT OF UNKNOWN SIGNIFICANCE. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at