chr7-5973397-G-A
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_000535.7(PMS2):c.*2C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. 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 0.0000088 ( 0 hom., cov: 19)
Exomes 𝑓: 0.0000073 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
PMS2
NM_000535.7 3_prime_UTR
NM_000535.7 3_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: -3.60
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 -5 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.92).
BP6
Variant 7-5973397-G-A is Benign according to our data. Variant chr7-5973397-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 187618.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PMS2 | NM_000535.7 | c.*2C>T | 3_prime_UTR_variant | 15/15 | ENST00000265849.12 | NP_000526.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PMS2 | ENST00000265849.12 | c.*2C>T | 3_prime_UTR_variant | 15/15 | 1 | NM_000535.7 | ENSP00000265849 | P3 |
Frequencies
GnomAD3 genomes AF: 0.00000883 AC: 1AN: 113238Hom.: 0 Cov.: 19
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GnomAD3 exomes AF: 0.00000501 AC: 1AN: 199490Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 108602
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000728 AC: 6AN: 824222Hom.: 0 Cov.: 11 AF XY: 0.00000700 AC XY: 3AN XY: 428388
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GnomAD4 genome AF: 0.00000883 AC: 1AN: 113294Hom.: 0 Cov.: 19 AF XY: 0.0000185 AC XY: 1AN XY: 53970
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 01, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Feb 06, 2024 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 25, 2015 | The c.*2C>T variant is located in the 3' untranslated region (3’UTR) of the PMS2 gene. This variant results from a C to T substitution 2 nucleotides after the termination codon of the PMS2 gene. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 5971 samples (11942 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.003% (greater than 65000 alleles tested) in our clinical cohort. This nucleotide position is poorly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of c.*2C>T remains unclear. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 24, 2018 | - - |
Computational scores
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BayesDel_noAF
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CADD
Benign
DANN
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at