rs142839559
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7
The NM_000535.7(PMS2):c.1242C>T(p.Asp414=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000558 in 1,614,148 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 Likely benign (★★).
Frequency
Genomes: 𝑓 0.00024 ( 1 hom., cov: 31)
Exomes 𝑓: 0.000036 ( 0 hom. )
Consequence
PMS2
NM_000535.7 synonymous
NM_000535.7 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.692
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 Benign. Variant got -13 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.9).
BP6
?
Variant 7-5987523-G-A is Benign according to our data. Variant chr7-5987523-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 187191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
Synonymous conserved (PhyloP=-0.692 with no splicing effect.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PMS2 | NM_000535.7 | c.1242C>T | p.Asp414= | synonymous_variant | 11/15 | ENST00000265849.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PMS2 | ENST00000265849.12 | c.1242C>T | p.Asp414= | synonymous_variant | 11/15 | 1 | NM_000535.7 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.000230 AC: 35AN: 152160Hom.: 1 Cov.: 31
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GnomAD3 exomes AF: 0.000127 AC: 32AN: 251110Hom.: 0 AF XY: 0.0000957 AC XY: 13AN XY: 135834
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GnomAD4 exome AF: 0.0000363 AC: 53AN: 1461870Hom.: 0 Cov.: 34 AF XY: 0.0000275 AC XY: 20AN XY: 727240
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GnomAD4 genome ? AF: 0.000243 AC: 37AN: 152278Hom.: 1 Cov.: 31 AF XY: 0.000363 AC XY: 27AN XY: 74452
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 08, 2014 | This alteration is classified as likely 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 01, 2016 | - - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jun 08, 2021 | - - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 24, 2022 | - - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 24, 2019 | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PMS2 p.Asp414= variant was not identified in the literature. The variant was identified in dbSNP (ID: rs142839559) as "With Likely benign allele" and in ClinVar (classified as benign by Invitae; and as likely benign by Ambry Genetics, Color and Integrated Genetics/Laboratory Corporation of America). The variant was identified in control databases in 37 of 277098 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 27 of 24012 chromosomes (freq: 0.001, increasing the likelihood this could be a low frequency benign variant), Other in 2 of 6458 chromosomes (freq: 0.0003), Latino in 6 of 34414 chromosomes (freq: 0.0002), and European in 2 of 126636 chromosomes (freq: 0.00002); it was not observed in the Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Asp414= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Lynch syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | - - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at