rs63751466

Positions:

Variant summary

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

The NM_000535.7(PMS2):c.2404C>T(p.Arg802Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000201 in 1,594,456 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. R802R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

PMS2
NM_000535.7 stop_gained

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:15

Conservation

PhyloP100: 0.747

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]

PMS2 links:

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 does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 29 pathogenic variants in the truncated region.

PP5

Variant 7-5977629-G-A is Pathogenic according to our data. Variant chr7-5977629-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 9237.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-5977629-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7 linkuse as main transcript	c.2404C>T	p.Arg802Ter	stop_gained	14/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12 linkuse as main transcript	c.2404C>T	p.Arg802Ter	stop_gained	14/15	1	NM_000535.7	P3	P54278-1

Frequencies

GnomAD3 genomes

AF:

0.0000134

AC:

AN:

149388

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000491

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000265

AC:

AN:

226074

Hom.:

AF XY:

0.0000325

AC XY:

AN XY:

123090

show subpopulations

Gnomad AFR exome

AF:

0.0000705

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000591

Gnomad SAS exome

AF:

0.000138

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000208

AC:

AN:

1445068

Hom.:

Cov.:

AF XY:

0.0000222

AC XY:

AN XY:

719120

show subpopulations

Gnomad4 AFR exome

AF:

0.0000603

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000509

Gnomad4 SAS exome

AF:

0.000222

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000637

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000134

AC:

AN:

149388

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

72706

show subpopulations

Gnomad4 AFR

AF:

0.0000491

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:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Lynch syndrome 4

Pathogenic:4

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. -
Pathogenic, no assertion criteria provided	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Oct 22, 2019	Seen as heterozygous in individuals with Lynch Syndrome homozygous in individuals with Constitutional Mismatch Repair deficiency. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 06, 2024	- -

Lynch syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 20, 2016	The p.Arg802X variant in PMS2 has been reported in 1 heterozygous individual with PMS2-associated tumors and 5 homozygous, consanguineous individuals with cafe-au-lait spots and PMS2-associated tumors. It segregated with disease in 6 affected homozygous siblings from 3 consanguineous families (De Vos 2004 & 2006, Senter 2008). However, none of the heterozygous parents from these consanguineous families had PMS2-associated tumors. Data from large population studies is insufficient to assess the frequency of this variant. This nonsense variant leads to a premature termination codon at position 802. This alteration occurs within the terminal 50 bases of the second to last exon and, therefore, may escape nonsense mediated decay (NMD) resulting in a truncated protein. In vitro functional studies provide some evidence that the p.Arg802X variant may impact protein function (Risinger 1995, Glaab 1998, Peron 2008, Li 2015). Loss of function of the PMS2 gene is an established disease mechanism in Lynch syndrome. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg802X variant is likely 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 -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 08, 2022	The c.2404C>T (p.R802*) alteration, located in exon 14 (coding exon 14) of the PMS2 gene, consists of a C to T substitution at nucleotide position 2404. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 802. This alteration occurs at the 3' terminus of the PMS2 gene and is not expected to trigger nonsense-mediated mRNA decay; however, it impacts the last 61 amino acids of the PMS2 protein and is expected to result in loss of function by premature protein truncation. This mutation was first reported in an endometrial carcinoma cell line and was observed to result in a truncated protein (Risinger, 1995). Furthermore, this alteration has been reported in multiple individuals with colorectal cancer, whose tumors showed loss of PMS2 on immunohistochemistry (IHC) (Senter, 2008; Rosty, 2016). This alteration has also been reported in a homozygous or compound heterozygous state with another PMS2 mutation in patients whose features include hematologic malignancies, brain tumors, and café-au-lait spots, which are consistent with the phenotype of biallelic PMS2 mutation carriers (De Vos, 2006; Plon, 2011; Andrianova, 2017). Based on the available evidence, this alteration is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Aug 10, 2021	- -

PMS2-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 04, 2023

The PMS2 c.2404C>T variant is predicted to result in premature protein termination (p.Arg802*). This variant has been reported in individuals with Lynch syndrome (Table 1, Senter et al. 2008. PubMed ID: 18602922; Table S2, ten Broeke et al. 2015. PubMed ID: 25512458; Table S2, Rosty. 2016. PubMed ID: 26895986; Table 1, Okkels et al. 2019. PubMed ID: 31433215; Table 2, Manchana and Triratanachat. 2021. PubMed ID: 34048176). It has been reported in a case of pediatric embryonal rhabdomyosarcoma (Table 3, referred to as 7:6017260G>A, Li et al. 2020. PubMed ID: 33372952). It has also been reported in the homozygous state and presumed compound heterozygous state in individuals with constitutional mismatch repair deficiency syndrome (De Vos et al. 2004. PubMed ID: 15077197; De Vos et al. 2006. PubMed ID: 16507833; Perez-Valencia et al. 2020. PubMed ID: 32773772; Gupta et al. 2020. PubMed ID: 32876971). This variant is reported in 6 of ~256,000 alleles in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/9237/). However, this region has high homology with the pseudogene PMS2CL, and data should be interpreted with caution (http://gnomad.broadinstitute.org/variant/7-6017260-G-A). Nonsense variants in PMS2 are known to be causative. This variant is interpreted 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

May 24, 2022

Variant summary: PMS2 c.2404C>T (p.Arg802X) 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 2.7e-05 in 226074 control chromosomes. c.2404C>T has been reported in the literature in heterozygous individuals affected with Lynch syndrome-related cancers (example Senter_2008, Rosty_2016, Suerink_2016, van der Klift_2016, Manchana_2021). In the homozygous state, the variant has also been observed in multiple individuals with early onset brain tumors, leukemias, and lymphomas, often with cooccurring cafe-au-lait spots (example De Vos_2004, De Vos_2006, Andrianova_2017). These data indicate that the variant is very likely to be associated with disease. An endometrial carcinoma cell line with the variant was found to only generate a truncated protein product and was deficient in mismatch repair, suggesting a negative impact on protein function (Risinger_1995). Six 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. -

Mismatch repair cancer syndrome 4

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2006

- -

Rhabdomyosarcoma

Pathogenic:1

Pathogenic, no assertion criteria provided

provider interpretation

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Sep 01, 2020

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 04, 2022

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 61 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Observed in the heterozygous state in individuals with Lynch syndrome-related tumors (Senter et al., 2008; Vaughn et al., 2010; Ten Broeke et al., 2015; Rosty et al., 2016; Andrianova et al., 2017; Manchana et al., 2021); 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: 15077197, 18602922, 18709565, 15340263, 17993636, 25512458, 25525159, 25691505, 17851451, 21376568, 20205264, 21356188, 28514183, 28152038, 26895986, 28805995, 32876971, 32029870, 31433215, 32773772, 30787465, 18619468, Fukui2011[Chapter], 34048176, 33372952, 16507833) -

Hereditary nonpolyposis colorectal neoplasms

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 12, 2024

This sequence change creates a premature translational stop signal (p.Arg802*) in the PMS2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 61 amino acid(s) of the PMS2 protein. The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This premature translational stop signal has been observed in individual(s) with Lynch syndrome-related cancers and childhood-onset hematological malignancies and brain tumors (PMID: 15077197, 16507833, 18602922, 25512458, 26110232, 26895986, 28805995). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9237). This variant disrupts a region of the PMS2 protein in which other variant(s) (p.Met834Glyfs*17) have been determined to be pathogenic (PMID: 2440087, 10037723, 21618646, 23012243). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Mismatch repair cancer syndrome 1

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Institute of Human Genetics, Medical University Innsbruck

May 06, 2020

This variant, NM_000535.6:c.2404C>T, was found in compound heterozygosity with the pathogenic variant NM_000535.6:c.736_741delinsTGTGTGTGAAG. Sample UAB620 in Perez J et al, Genet Med (PMID: 32773772). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.26

Eigen_PC

Benign

0.084

FATHMM_MKL

Uncertain

0.80

MutationTaster

Benign

1.0

A;A;A;A

Vest4

0.97

GERP RS

2.9

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over