7-5987205-C-T
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Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2
The NM_000535.7(PMS2):c.1560G>A(p.Ala520Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000454 in 1,614,100 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A520A) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00046 ( 2 hom. )
Consequence
PMS2
NM_000535.7 synonymous
NM_000535.7 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.210
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 -10 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.72).
BP6
Variant 7-5987205-C-T is Benign according to our data. Variant chr7-5987205-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 138700.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=9, Uncertain_significance=1, Benign=4}. Variant chr7-5987205-C-T is described in Lovd as [Likely_benign]. Variant chr7-5987205-C-T is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-0.21 with no splicing effect.
BS2
High Homozygotes in GnomAdExome4 at 2 AD,AR gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PMS2 | NM_000535.7 | c.1560G>A | p.Ala520Ala | synonymous_variant | 11/15 | ENST00000265849.12 | NP_000526.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PMS2 | ENST00000265849.12 | c.1560G>A | p.Ala520Ala | synonymous_variant | 11/15 | 1 | NM_000535.7 | ENSP00000265849.7 |
Frequencies
GnomAD3 genomes 0.000388 AC: 59AN: 152142Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000342 AC: 86AN: 251250Hom.: 0 AF XY: 0.000331 AC XY: 45AN XY: 135840
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GnomAD4 exome AF: 0.000461 AC: 674AN: 1461840Hom.: 2 Cov.: 44 AF XY: 0.000465 AC XY: 338AN XY: 727222
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GnomAD4 genome 0.000387 AC: 59AN: 152260Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34AN XY: 74436
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:17
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:6
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 26, 2017 | Variant summary: The c.1560G>A (p.Ala520=) in PMS2 gene is a synonymous change that involves a non-conserved nucleotide. 4/5 programs in Alamut predict that this variant does not affect the normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population datasets of ExAC and gnomAD at a similar frequencies 0.00033 (38/120402 and 93/277018 chrs tested, respectively), which is about 3 times of the maximum expected allele frequency for a pathogenic PMS2 variant (0.00011). Sequence allignment and reads in ExAC support that the minor alleles reported in ExAC are not from the pseudogene. The variant has not, to our knowledge, been reported in affected individuals via published reports but is cited as Benign/Likely Benign by reputable databases/clinical laboratories. Taking together, the variant was classified as benign. - |
| Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 09, 2023 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | PMS2: BP4, BP7 - |
| Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 12, 2023 | - - |
| Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Hereditary cancer-predisposing syndrome Benign:4
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 15, 2015 | - - |
| Likely benign, no assertion criteria provided | clinical testing | True Health Diagnostics | Sep 27, 2017 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 23, 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 | curation | Sema4, Sema4 | Apr 11, 2021 | - - |
not specified Benign:3
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 22, 2014 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
| Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 05, 2019 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Lynch syndrome 4 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Breast and/or ovarian cancer Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jun 22, 2023 | - - |
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 | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | - - |
Malignant tumor of breast Benign:1
| Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PMS2 p.Ala520= variant was not identified in the literature nor was it identified in the following databases: COGR, Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs201167814) “With Uncertain significance allele”, ClinVar (classified benign by GeneDx, likely benign by Ambry Genetics, Invitae, Color Genomics Inc, Quest Diagnostics Nichols Institute San Juan Capistrano, and uncertain significance by Praxis fuer Humangenetik Tuebingen), Clinvitae (4x), and in control databases in 93 of 277018 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 23986 chromosomes (freq: 0.00004), “Other” in 2 of 6464 chromosomes (freq: 0.0003), Latino in 16 of 34418 chromosomes (freq: 0.0005), European Non-Finnish in 66 of 126586 chromosomes (freq: 0.0005), East Asian in 4 of 18864 chromosomes (freq: 0.0002), European Finnish in 2 of 25782 chromosomes (freq: 0.00008), and South Asian in 2 of 30782 chromosomes (freq: 0.00007); it was not observed in the Ashkenazi Jewish population. The p.Ala520= variant is not expected to have clinical significance because it does not result in a change of amino acid. This variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. - |
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