7-6002515-C-T
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6
The NM_000535.7(PMS2):c.475G>A(p.Val159Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000664 in 1,611,592 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V159L) has been classified as Uncertain significance.
Frequency
Consequence
NM_000535.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PMS2 | NM_000535.7 | c.475G>A | p.Val159Met | missense_variant | 5/15 | ENST00000265849.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PMS2 | ENST00000265849.12 | c.475G>A | p.Val159Met | missense_variant | 5/15 | 1 | NM_000535.7 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152170Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000638 AC: 16AN: 250682Hom.: 0 AF XY: 0.0000738 AC XY: 10AN XY: 135566
GnomAD4 exome AF: 0.0000671 AC: 98AN: 1459422Hom.: 0 Cov.: 30 AF XY: 0.0000620 AC XY: 45AN XY: 726052
GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74336
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 02, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal and/or family history of colorectal, breast, prostate, or stomach cancer (Chubb et al., 2015; Lu et al., 2015; Haraldsdottir et al., 2017; Yehia et al., 2018; Stuttgen et al., 2019; Akcay et al., 2020; Matejcic et al., 2020); This variant is associated with the following publications: (PMID: 25559809, 26689913, 28466842, 29684080, 28873162, 29354287, 31391288, 31465090, 11574484, 32832836, 32658311) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 02, 2023 | In the published literature, the variant has been reported in individuals affected with colorectal cancer (PMIDs: 25559809 (2015), 28466842 (2017)), stomach adenocarcinoma (PMIDs: 26689913 (2015)), and breast cancer (PMIDs: 32658311 (2021), 26689913 (2015), 31465090 (2019)). In a large breast cancer association study, the variant was reported in both cases and controls (PMID: 33471991 (2021), https://databases.lovd.nl/shared/variants/PMS2). The frequency of this variant in the general population, 0.00012 (16/128726 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Lynch syndrome 4 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 31, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Human Genetics Bochum, Ruhr University Bochum | Feb 20, 2023 | ACMG criteria used to clasify this variant:PS4_MOD, PM2_SUP, PP3 - |
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 20, 2022 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 21, 2023 | This missense variant replaces valine with methionine at codon 159 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with colorectal cancer (PMID: 25559809), stomach adenocarcinoma (PMID: 26689913), and breast cancer (PMID: 26689913, 29684080, 31465090). This variant has been identified in 17/245638 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Aug 04, 2023 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Feb 06, 2024 | - - |
Carcinoma of colon Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PMS2 p.Val159Met variant was not identified in the literature nor was it identified in the GeneInsight-COGR, Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, databases. The variant was identified in dbSNP (ID: rs142416537) “With Uncertain significance allele”, ClinVar (as uncertain significance by GeneDx, Invitae and Ambry Genetics), Clinvitae (4x), Insight Hereditary Tumors Database (1x), and in control databases in 17 of 245638 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European Non-Finnish in 16 of 111290 chromosomes (freq: 0.0001), European Finnish in 1 of 22242 chromosomes (freq: 0.00005), while not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, and South Asian populations. The p.Val159 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Met to the protein; this information is not very predictive of pathogenicity. The 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. This variant is classified as a variant of uncertain significance. - |
Lynch syndrome 4;C5399763:Mismatch repair cancer syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
PMS2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 29, 2024 | The PMS2 c.475G>A variant is predicted to result in the amino acid substitution p.Val159Met. This variant was reported as a variant of uncertain significance in an individual with breast cancer (Stuttgen et al. 2019. PubMed ID: 31465090) and was also reported in cohorts of individuals with colorectal cancer (Chubb et al. 2015. PubMed ID: 25559809, Table A1; Haraldsdottir et al. 2017. PubMed ID: 28466842). Additionally, this variant was reported in an individual with stomach adenocarcinoma (Lu et al. 2015. PubMed ID: 26689913, supplementary table 12) and in a cohort of individuals with cancer (Yehia et al. 2018. PubMed ID: 29684080, Table S9). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In the ClinVar database, this variant has been listed as 'uncertain' or 'likely benign' by multiple outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/127791/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Lynch syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 01, 2023 | This missense variant replaces valine with methionine at codon 159 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with colorectal cancer (PMID: 25559809), stomach adenocarcinoma (PMID: 26689913), and breast cancer (PMID: 26689913, 29684080, 31465090). This variant has been identified in 17/245638 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. - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at