7-5987504-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000535.7(PMS2):​c.1261C>T​(p.Arg421*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,614,056 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 (★★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PMS2
NM_000535.7 stop_gained

Scores

2
3
2

Clinical Significance

Pathogenic reviewed by expert panel P:16O:1

Conservation

PhyloP100: 1.21
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 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-5987504-G-A is Pathogenic according to our data. Variant chr7-5987504-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 91299.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-5987504-G-A is described in Lovd as [Pathogenic]. Variant chr7-5987504-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PMS2NM_000535.7 linkc.1261C>T p.Arg421* stop_gained Exon 11 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.1261C>T p.Arg421* stop_gained Exon 11 of 15 1 NM_000535.7 ENSP00000265849.7 P54278-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152196
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461860
Hom.:
0
Cov.:
34
AF XY:
0.00000138
AC XY:
1
AN XY:
727224
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
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:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152196
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
74364
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
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:
0.0000189
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:16Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Lynch syndrome Pathogenic:3
Sep 05, 2013
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Significance: Pathogenic
Review Status: reviewed by expert panel
Collection Method: research

Coding sequence variation resulting in a stop codon -

Mar 03, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.Arg421X variant in PMS2 has been reported in one carrier with unspecified phenotype (Suerink 2015), and was absent from large population studies. This non sense variant leads to a premature termination codon at position 421, which is p redicted to lead to a truncated or absent protein. Heterozygous loss of function of the PMS2 gene is an established disease mechanism in Lynch syndrome. In summ ary, this variant meets our criteria to be classified as pathogenic for Lynch sy ndrome in an autosomal dominant manner based upon the predicted impact to the pr otein. -

Jun 09, 2024
All of Us Research Program, National Institutes of Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant changes 1 nucleotide in exon 11/15 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 suspected of having Lynch syndrome (PMID: 23012243, 26110232). This variant has not been identified 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. -

not provided Pathogenic:3
Sep 04, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Observed in individuals with suspected Lynch Syndrome (PMID: 23012243, 26110232, 31992580); 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; Not observed at significant frequency in large population cohorts (gnomAD); 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: 31159747, 24728327, 26110232, 23012243, 31589614, 30787465, 31992580, 33259954, 33693762, 35988656) -

May 28, 2024
Mayo Clinic Laboratories, Mayo Clinic
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PP4, PVS1 -

Jul 01, 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, 0.0000066 (1/152196 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast and/or ovarian cancer (PMID: 31300551 (2020), 31159747 (2019), 29345684 (2018)), and Lynch syndrome (PMID: 26110232 (2016), 23012243 (2013)). Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:3
Jan 15, 2020
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 11 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 not been identified 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. -

Apr 06, 2022
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.R421* pathogenic mutation (also known as c.1261C>T), located in coding exon 11 of the PMS2 gene, results from a C to T substitution at nucleotide position 1261. This changes the amino acid from an arginine to a stop codon within coding exon 11. This pathogenic alteration was present in 1/130 European families with PMS2 mutations meeting either Bethesda criteria or "MSI-testing-indicated-by-a-pathologist" criteria (Suerink M et al. Genet. Med. 2016 Apr;18:405-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Jan 01, 2020
GeneKor MSA
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This is a point mutation replacing one nucleotide in the position 1261 of the PMS2 gene, leading in the replacement of Arginine with a termination stop codon in the position 421 of the PMS2 protein. The resulting protein is truncated and non functional. This particular variant has been described in international literature in families with colorectal cancer and/or Lynch syndrome (PMID: 23012243, PMID: 26110232). The mutation database ClinVar contains an entry for this variant (Variation ID: 91299). -

Lynch syndrome 4 Pathogenic:3
Sep 20, 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. -

May 18, 2023
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 27, 2018
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Hereditary nonpolyposis colon cancer Pathogenic:1
Aug 04, 2023
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.1261C>T (p.Arg421X) 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. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251060 control chromosomes. c.1261C>T has been reported in the literature in individuals with suspected Hereditary Nonpolyposis Colorectal Cancer (e.g. Vaughn_2013, Suerink_2016). It has also been reported by different studies in a number of individuals affected with breast cancer (e.g. Roberts_2018, Tsaousis_2019, Fostira_2020), with one of the studies concluding that pathogenic variants in the PMS2 gene are associated with an increased risk for breast cancer following retrospective review of patient data (Roberts_2018). 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. The following publications have been ascertained in the context of this evaluation (PMID: 23012243, 29345684, 26110232, 31159747, 31300551). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Lynch syndrome 4;C5436817:Mismatch repair cancer syndrome 4 Pathogenic:1
Jun 10, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Jan 12, 2025
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.Arg421*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with colorectal cancer and/or suspected Lynch syndrome (PMID: 23012243, 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: 91299). For these reasons, this variant has been classified as Pathogenic. -

Endometrial carcinoma Pathogenic:1
-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The p.ARG421X variant was identified as a nonsense mutation in the paper by Topp (2014). The variant was also identified in COSMIC in large intestine tissue and InSiGHT Colon Cancer databases. In ClinVar the variant was classified as pathogenic by InSiGHT. This residue is not conserved in mammals and computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM) have not provided predictions regarding the impact to the protein. In summary, based on the above information this variant meets our laboratory's criteria to be classified as pathogenic. -

not specified Other:1
Sep 19, 2013
ITMI
Significance: not provided
Review Status: no classification provided
Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.55
CADD
Pathogenic
37
DANN
Uncertain
1.0
Eigen
Uncertain
0.20
Eigen_PC
Benign
-0.00042
FATHMM_MKL
Uncertain
0.84
D
Vest4
0.94
GERP RS
-1.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.10
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: rs587778617; hg19: chr7-6027135; COSMIC: COSV56224693; API