rs730881919

Positions:

• chr7-6003981-C-A
• chr7-6003981-C-G
• chr7-6003981-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2_Supporting PVS1

This summary comes from the ClinGen Evidence Repository: The c.241G>T (p.Glu81Ter) (NM_000535.7) variant in PMS2 is a nonsense variant predicted to cause a premature stop codon in exon 3 in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is extremely rare (1 in 1594104 alleles) in gnomAD v4.1 (PM2_Supporting).In summary, this variant meets the criteria to be classified as likely pathogenic for Lynch-Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/ Polyposis VCEP: PVS1, PM2_SUP (VCEP specifications version 1) LINK:https://erepo.genome.network/evrepo/ui/classification/CA366744765/MONDO:0007356/139

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PMS2 NM_000535.7 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 5.76

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7	c.241G>T	p.Glu81Ter	stop_gained	3/15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.241G>T	p.Glu81Ter	stop_gained	3/15	1	NM_000535.7	ENSP00000265849	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250820 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135658

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00000139 AC: 2 AN: 1441888 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 718704

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lynch syndrome 4 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 11, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 20, 2023	The PMS2 c.241G>T (p.Glu81Ter) nonsense variant results in the loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been identified in an individual with colorectal cancer, whose tumor cells also lacked PMS2 protein expression (PMID: 27589204). Additionally, the p.Glu81Ter variant was reported in a compound heterozygous state in two individuals with constitutional mismatch repair deficiency and a family history of cancer (PMID: 36647049). This variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Based on the available evidence, the c.241G>T (p.Glu81Ter) variant is classified as pathogenic for Lynch syndrome. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Sep 28, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 03, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2023	Observed in an individual with a personal history consistent with pathogenic variants in this gene (PMID: 27589204); 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: 36988593, 21376568, 24362816, 29922827, 27589204, 36647049) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 06, 2023	The PMS2 c.241G>T (p.Glu81*) variant causes the premature termination of PMS2 protein synthesis. This variant has been reported in the published literature in individuals affected with colorectal cancer (PMID: 27589204 (2016)) and CMMRD (PMID: 36647049 (2023)). The frequency of this variant in the general population, 0.000004 (1/250820 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 21, 2024	The p.E81* pathogenic mutation (also known as c.241G>T), located in coding exon 3 of the PMS2 gene, results from a G to T substitution at nucleotide position 241. This changes the amino acid from a glutamic acid to a stop codon within coding exon 3. This mutation has been identified in a Japanese colorectal cancer cohort (Sugano K et al. Cancer Sci, 2016 Nov;107:1677-1686). 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	Apr 11, 2023	This variant changes 1 nucleotide in exon 3 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 observed in an individual affected with colorectal cancer demonstrating high microsatellite instability (PMID: 27589204). This variant has also been reported in the compound heterozygous state in two unrelated individuals affected with constitutional mismatch repair deficiency (PMID: 36647049). This variant has been identified in 1/250820 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. -

Hereditary nonpolyposis colon cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 23, 2023

Variant summary: PMS2 c.241G>T (p.Glu81X) 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 4e-06 in 250820 control chromosomes, however due to the PMS2 pseudogene these results should be interpreted with caution (gnomAD). c.241G>T has been reported in the literature in an individual affected with colorectal cancer with a MSI-H tumor lacking PMS2 expression by IHC, and in the compound heterozygous state in two unrelated individuals affected with constitutional mismatch repair deficiency (CMMRD) wherein glioblastoma was the initial CMMRD-associated malignancy and the variant was confirmed to be in trans with large PMS2 deletions (Sugano_2016, Onishi_2023). These data indicate that the variant is very likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as either pathogenic (n=4) or likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. -

Lynch syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Department of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center

Nov 08, 2022

This sequence change is nonsense variant introducing Premature Termination Codon. This variant has been detected in patients who developed MSI-H glioblastoma at age 10 or younger, along with another variant, PMS2(NM_000535.7): c.2276-125_2445+1584del (exon 14 deletion, phase unknown).It has also been detected in patients under 20 years of age with PMS2-deficient glioblastoma and colorectal adenocarcinoma in IHC, along with another variant, NC_000007.13: g.5876369_612205del (large deletions including PMS2 gene, located in trans). These two patients are considered constitutional mismatch repair deficiency (CMMRD). -

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 07, 2024

This sequence change creates a premature translational stop signal (p.Glu81*) 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 (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with colorectal cancer (PMID: 27589204). ClinVar contains an entry for this variant (Variation ID: 439243). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A;A;A;N
Vest4		0.92
ClinPred		0.65	D
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs730881919; hg19: chr7-6043612;