rs587780062

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000535.7(PMS2):​c.823C>T​(p.Gln275*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,612,770 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. Q275Q) has been classified as Pathogenic. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

PMS2
NM_000535.7 stop_gained

Scores

2
1
4

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:19

Conservation

PhyloP100: 1.62
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 7-5995614-G-A is Pathogenic according to our data. Variant chr7-5995614-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 127796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5995614-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PMS2NM_000535.7 linkc.823C>T p.Gln275* stop_gained Exon 8 of 15 ENST00000265849.12 NP_000526.2 P54278-1Q7Z3Q2B4DGM0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PMS2ENST00000265849.12 linkc.823C>T p.Gln275* stop_gained Exon 8 of 15 1 NM_000535.7 ENSP00000265849.7 P54278-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152192
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000656
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251410
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135874
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000411
AC:
6
AN:
1460578
Hom.:
0
Cov.:
30
AF XY:
0.00000275
AC XY:
2
AN XY:
726680
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152192
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74330
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000656
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:19
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Lynch syndrome 4 Pathogenic:6
Oct 22, 2023
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 26, 2017
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This c.823C>T (p.Gln275*) variant in the PMS2 gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple patients with cancer (PMID: 22848017, 25512458, 24689082, 26681312). The c.823C>T (p.Gln275*) variant in the PMS2 gene is classified as pathogenic. -

Apr 26, 2021
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

ACMG codes:PVS1; PS4M; PM2; PP5 -

May 02, 2022
MGZ Medical Genetics Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 19, 2023
Myriad Genetics, Inc.
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Jun 23, 2024
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The PMS2 c.823C>T (p.Gln275Ter) change is a nonsense variant that is predicted to cause premature protein truncation or absence of protein due to nonsense-mediated decay. This variant has been reported in individuals with Lynch-syndrome associated cancers (PMID: 27435373, 31992580). This variant has also been reported in conjunction with another pathogenic variant in an individual with constitutional mismatch repair deficiency (PMID: 22848017). This variant has a maximum subpopulation frequency of 0.006% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic. -

not provided Pathogenic:5
Aug 05, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium; This variant is associated with the following publications: (PMID: 24689082, 26681312, 28514183, 26110232, 23012243, 25512458, 31992580, 31447099, 30787465, 33087929, 22848017) -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dec 18, 2022
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This nonsense variant causes the premature termination of PMS2 protein synthesis. The frequency of this variant in the general population, 0.000008 (2/251410 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with Lynch syndrome (PMIDs: 31992580 (2020), 25512458 (2015), 23012243 (2013)). Based on the available information, this variant is classified as pathogenic. -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Aug 03, 2022
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Lynch syndrome Pathogenic:2
Dec 13, 2023
All of Us Research Program, National Institutes of Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.823C>T (p.Gln275*) variant in the PMS2 gene is located on the exon 8 and introduces a premature translation termination codon (p.Gln275*), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with Lynch syndrome-associated cancer or constitutional mismatch repair-deficiency syndrome (PMID: 28514183, 24689082, 27435373, 26110232, 23012243, 22848017). Loss-of-function variants in PMS2 are known to be pathogenic and variants located downstream to this position in this exon have been reported as pathogenic (PMID: 28514183, 25512458, 35223509, p.Gln288fs, ClinVar ID: 91376). The variant is reported in ClinVar (ID: 127796). The variant is rare in the general population according to gnomAD (2/251410). Therefore, the c.823C>T (p.Gln275*) variant of PMS2 has been classified as pathogenic. -

Oct 14, 2019
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.Gln275X variant in PMS2 has been reported in at least 4 heterozygous individuals with PMS2-associated cancers and in 1 compound heterozygous individual with constitutive mismatch repair deficiency (Espenschied 2017, Susswein 2016, Suerink 2016, Hansen 2014, Vaughn 2013, Yeung 2013). This variant has been identified in 2/34590 of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (pathogenic by several clinical labs (ClinVar ID 127796). This nonsense variant leads to a premature termination codon at position 275, 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. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting, PM3. -

Hereditary cancer-predisposing syndrome Pathogenic:2
Sep 05, 2023
Color Diagnostics, LLC DBA Color Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant changes 1 nucleotide in exon 8 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 an individual affected with constitutional mismatch mismatch repair deficiency who also carried another pathogenic PMS2 variant in trans (PMID: 22848017), as well as in multiple individuals affected with Lynch syndrome (PMID: 25512458, 27435373, 31992580). This variant has been identified in 2/251410 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. -

Jan 11, 2022
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.Q275* pathogenic mutation (also known as c.823C>T), located in coding exon 8 of the PMS2 gene, results from a C to T substitution at nucleotide position 823. This changes the amino acid from a glutamine to a stop codon within coding exon 8. This mutation has been reported in two Hereditary Non-Polyposis Colorectal Cancer (HNPCC)/Lynch syndrome families in the Netherlands (ten Broeke SW et al. J. Clin. Oncol. 2015 Feb;33(4):319-25); in a child diagnosed with constitutional mismatch repair deficiency (CMMR-D) who also had a second PMS2 mutation (Yeung JT et al. Pediatr Blood Cancer. 2013 Jan;60(1):137-9); and in a patient with endometrial cancer (Susswein LR et al. Genet. Med. 2016 Aug;18(8):823-32). 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. -

Lynch syndrome 4;C5399763:Mismatch repair cancer syndrome 1 Pathogenic:1
Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary nonpolyposis colon cancer Pathogenic:1
Oct 28, 2020
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: PMS2 c.823C>T (p.Gln275X) 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 8e-06 in 251410 control chromosomes (gnomAD). c.823C>T has been reported in the literature in multiple individuals affected with colorectal cancer and Lynch syndrome (Yeung_2013, Hansen_2014, ten Broeke_2015, van der Klift_2016, Wang_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Lynch syndrome 4;C5436817:Mismatch repair cancer syndrome 4 Pathogenic:1
Apr 15, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Aug 19, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln275*) 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 (rs587780062, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome, and constitutional mismatch repair deficiency (PMID: 23012243, 24689082, 26110232). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this PMS2 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for PMS2 testing. ClinVar contains an entry for this variant (Variation ID: 127796). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Pathogenic
0.31
CADD
Pathogenic
36
DANN
Uncertain
0.99
Eigen
Benign
-0.070
Eigen_PC
Benign
-0.37
FATHMM_MKL
Benign
0.15
N
Vest4
0.92
GERP RS
0.60

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.13
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587780062; hg19: chr7-6035245; COSMIC: COSV56219600; API