7-5987522-C-T
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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.1243G>A(p.Val415Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000165 in 1,614,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V415L) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.00019 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00016 ( 0 hom. )
Consequence
PMS2
NM_000535.7 missense
NM_000535.7 missense
Scores
19
Clinical Significance
Conservation
PhyloP100: 0.453
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 (MetaRNN=0.04859841).
BP6
Variant 7-5987522-C-T is Benign according to our data. Variant chr7-5987522-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 142561.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=6, Benign=2, not_provided=1}. Variant chr7-5987522-C-T is described in Lovd as [Likely_benign].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| PMS2 | NM_000535.7 | c.1243G>A | p.Val415Met | missense_variant | 11/15 | ENST00000265849.12 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| PMS2 | ENST00000265849.12 | c.1243G>A | p.Val415Met | missense_variant | 11/15 | 1 | NM_000535.7 | P3 |
Frequencies
GnomAD3 genomes 0.000191 AC: 29AN: 152134Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000159 AC: 40AN: 251130Hom.: 0 AF XY: 0.000213 AC XY: 29AN XY: 135832
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GnomAD4 exome AF: 0.000162 AC: 237AN: 1461884Hom.: 0 Cov.: 34 AF XY: 0.000182 AC XY: 132AN XY: 727242
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GnomAD4 genome 0.000190 AC: 29AN: 152252Hom.: 0 Cov.: 31 AF XY: 0.000228 AC XY: 17AN XY: 74442
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:6Benign:10Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:5
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 03, 2021 | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with personal or family history of breast, ovarian, pancreatic, or other cancer (Lu 2015, Zhang 2015, Hu 2016, Yadav 2016, Cock-Rada 2017); This variant is associated with the following publications: (PMID: 22941189, 27846281, 26689913, 26483394, 26580448, 27878467, 28528518, 31433215, 31391288, 31422574, 31327751, 25567908) - |
| Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 08, 2022 | - - |
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | PMS2: BP4 - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
| Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 05, 2022 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 16, 2016 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 29, 2019 | 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. - |
Lynch syndrome 4 Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Aug 30, 2022 | The PMS2 c.1243G>A (p.Val415Met) missense change has a maximum subpopulation frequency of 0.028% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in at least one individual with colorectal cancer and/or Lynch syndrome (PMID: 31433215). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. - |
| 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. - |
not specified Uncertain:1Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 31, 2023 | Variant summary: PMS2 c.1243G>A (p.Val415Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The observed variant frequency is approximately 2.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Lynch Syndrome phenotype (0.00011), strongly suggesting that the variant is benign. However, the variant is located in a region that is highly homologous to PMS2 pseudogene and the technology utilized for these datasets does not rule out pseudogene interference, therefore these data might not be reliable. c.1243G>A has been reported in the literature in sequencing studies of individuals affected with cancer including pancreatic cancer, acute megakaryoblastic leukemia, breast and/or ovarian cancer and colon cancer (e.g. Hu_2022, Guindalini_2022, Cock-Rada 2018, Hu 2016, Lu_2015, Okkels_2019, Yadav 2017, Zhang 2015). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. The following publications have been ascertained in the context of this evaluation (PMID: 26483394, 26689913, 25567908, 27878467, 28528518, 26580448, 31422574, 31433215). 11 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=5; likely benign, n=4; Benign, n=2). Based on the evidence outlined above, the variant was classified as likely benign. - |
Hereditary breast ovarian cancer syndrome Uncertain:1
| Uncertain significance, no assertion criteria provided | in vivo | Oncological Genetic Counseling Clinic, "Carlo Poma" Hospital | Aug 16, 2022 | - - |
Endometrial carcinoma Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PMS2 p.Val415Met variant was identified in 3 of 456 proband chromosomes (frequency: 0.007) from individuals or families with lung adenocarcinoma, breast, ovarian or pancreatic cancer (Cock-Rada 2018, Drilon 2016, Hu 2016). The variant was also identified in dbSNP (ID: rs138387687 as "With Uncertain significance allele"), ClinVar (classified as likely benign by Ambry Genetics; as uncertain significance by Invitae, GeneDx, and Integrated Genetics/Laboratory Corporation of America), and Cosmic (3x in lung, stomach or salivary gland). The variant was not identified in GeneInsight-COGR, MutDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was identified in control databases in 44 of 277090 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24008 chromosomes (freq: 0.00004), Latino in 10 of 34418 chromosomes (freq: 0.0003), European in 32 of 126634 chromosomes (freq: 0.0003), and Finnish in 1 of 25792 chromosomes (freq: 0.00004), while the variant was not observed in the Other, Ashkenazi Jewish, East Asian, or South Asian populations. The p.Val415 residue is not conserved in mammals and 4 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 4 of 4 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. This variant is classified as a variant of uncertain significance. - |
Hereditary nonpolyposis colon cancer Benign:1
| Benign, criteria provided, single submitter | clinical testing | Mendelics | Aug 22, 2023 | - - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
Lynch syndrome 4;C5399763:Mismatch repair cancer syndrome 1 Other:1
| not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Likely benign and reported on 06-15-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;.;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T;.;T;.
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;.;.;.
MutationTaster
Benign
N;N;N;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;N;.;.;.
REVEL
Benign
Sift
Benign
T;T;.;.;.
Sift4G
Benign
T;T;.;.;.
Polyphen
P;P;.;.;P
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
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