rs200640585
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000535.7(PMS2):c.943C>T(p.Arg315Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,601,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. R315R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000535.7 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PMS2 | NM_000535.7 | c.943C>T | p.Arg315Ter | stop_gained | 9/15 | ENST00000265849.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PMS2 | ENST00000265849.12 | c.943C>T | p.Arg315Ter | stop_gained | 9/15 | 1 | NM_000535.7 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152052Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251270Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135844
GnomAD4 exome AF: 0.0000138 AC: 20AN: 1449776Hom.: 0 Cov.: 27 AF XY: 0.0000111 AC XY: 8AN XY: 722030
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 152052Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74274
ClinVar
Submissions by phenotype
Lynch syndrome Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 31, 2020 | Variant summary: PMS2 c.943C>T (p.Arg315X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.6e-05 in 251270 control chromosomes. c.943C>T has been reported in the literature in individuals affected with Lynch Syndrome or breast cancer (Susswein_2016, Latham_2019). These data indicate that the variant is likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Sep 05, 2013 | Coding sequence variation resulting in a stop codon - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 05, 2024 | This variant changes 1 nucleotide in exon 9 of the PMS2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with Lynch syndrome (PMID: 30376427) and colorectal cancer with tumors showing loss of PMS2 expression and/or microsatellite instability (PMID: 20205264, 22918162, 23709753, 25856668, 27589204). This variant has also been reported in an individual affected with breast cancer (PMID: 28724667). This variant has been identified in 5/282632 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 27, 2021 | The p.Arg315X variant in PMS2 has been reported in at least 9 individuals with PMS2-associated cancers and segregated with disease in at least 2 affected individuals from one family (Vaughn 2010 PMID: 20205264, Borras 2013 PMID: 23709753, Sugano 2016 PMID: 27589204, Susswein 2016 PMID: 26681312, Sun 2017 PMID: 28724667, Jiang 2019 PMID: 30521064, Lerner-Ellis 2021 PMID: 32885271, Wang 2020 PMID: 31992580). It has also been identified in 0.01% (1/10366) of Ashkenazi Jewish chromosomes, 0.005% (1/19950) of East Asian chromosomes and 0.004% (1/24956) of Afircan/African-American chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 315, which is predicted to lead to a truncated or absent protein. Loss of function of the PMS2 gene is an established disease mechanism in autosomal dominant Lynch syndrome. Additionally, this variant was classified as pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 91382). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PS4_Moderate. - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 04, 2021 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with MSI-H and/or PMS2 absent colorectal cancer (Vaughn 2010, Borras 2013, Shia 2013, Hinrichsen 2015, Goodenberger 2016, Sugano 2016, Wang 2020); Published functional studies demonstrate a damaging effect: loss of PMS2 expression and reduced MMR activity (Hinrichsen 2015); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 32885271, 32719484, 25477341, 23709753, 20205264, 22918162, 25856668, 27589204, 31992580, 31784482, 31297337, 30521064, 26681312, 28724667, 25111426, 26046366, 25430799, 25525159, 25637381) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 07, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 16, 2022 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 27, 2022 | The p.R315* pathogenic mutation (also known as c.943C>T), located in coding exon 9 of the PMS2 gene, results from a C to T substitution at nucleotide position 943. This changes the amino acid from an arginine to a stop codon within coding exon 9. This mutation has been reported in multiple individuals with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome; several whose tumors demonstrated high microsatellite instability and/or absent PMS2 by immunohistochemistry (IHC) (Vaughn CP et al. Hum Mutat, 2010 May;31:588-93; Shia J et al. Mod. Pathol., 2013 Jan;26:131-8; Borràs E et al. J Med Genet, 2013 Aug;50:552-63; Goldberg Y et al. Clin Genet, 2015 Jun;87:549-53; Sugano K et al. Cancer Sci, 2016 Nov;107:1677-1686; Goodenberger ML et al. Genet Med, 2016 Jan;18:13-9; Jiang W et al. Int J Cancer, 2019 05;144:2161-2168; Guo X et al. Mol Genet Genomic Med, 2019 06;7:e721; Maynard H et al. Cancer, 2020 01;126:1995-2002; Wang Q et al. J Med Genet, 2020 07;57:487-499; Choi YY et al. Sci Rep, 2021 07;11:14807). This mutation was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome. The individual was diagnosed with breast cancer at age 44 (Lerner-Ellis J et al. J Cancer Res Clin Oncol. 2021 147, 871–879). Pathogenicity of this mutation has been supported by a functional assay showing reduced mismatch repair activity in vitro and lack of full length PMS2 protein expression (Hinrichsen I et al. Carcinogenesis. 2015 Feb;36:202-11). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 08, 2024 | This variant changes 1 nucleotide in exon 9 of the PMS2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with Lynch syndrome (PMID: 30376427) and colorectal cancer with tumors showing loss of PMS2 expression and/or microsatellite instability (PMID: 20205264, 22918162, 23709753, 25856668, 27589204). This variant has also been reported in an individual affected with breast cancer (PMID: 28724667). This variant has been identified in 5/282632 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 25, 2020 | - - |
Lynch syndrome 4 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Oct 02, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 03, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 05, 2023 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
Lynch syndrome 4;C5399763:Mismatch repair cancer syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Colorectal cancer, non-polyposis Pathogenic:1
Pathogenic, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Gastric cancer Pathogenic:1
Pathogenic, no assertion criteria provided | research | Laboratory for Genotyping Development, RIKEN | Jul 01, 2021 | - - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | This sequence change creates a premature translational stop signal (p.Arg315*) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). This variant is present in population databases (rs200640585, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome and colon cancer (PMID: 20205264, 22918162, 23709753, 25856668, 27589204). ClinVar contains an entry for this variant (Variation ID: 91382). For these reasons, this variant has been classified as Pathogenic. - |
Malignant tumor of breast Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PMS2 p.Arg315* variant was identified in 5 of 2648 proband chromosomes (frequency: 0.002) from individuals or families with Lynch syndrome (Borras 2013, Goldberg 2015, Goodenberger 2016, Sugano 2016, Vaughn 2010). The variant was also identified in dbSNP (ID: rs200640585) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx and four other submitters). The variant was identified in control databases in 6 of 277038 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24022 chromosomes (freq: 0.00004), European in 3 of 126694 chromosomes (freq: 0.00002), Ashkenazi Jewish in 1 of 10150 chromosomes (freq: 0.0001), and East Asian in 1 of 18866 chromosomes (freq: 0.00005); it was not observed in the Other, Latino, Finnish, or South Asian populations. The p.Arg315* variant leads to a premature stop codon at position 315, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PMS2 gene are an established mechanism of disease in Lynch syndrome and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at