rs63750871

Positions:

Variant summary

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

The NM_000535.7(PMS2):c.400C>T(p.Arg134Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000496 in 1,611,750 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 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

PMS2
NM_000535.7 stop_gained

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:20

Conservation

PhyloP100: 5.96

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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 7-6002590-G-A is Pathogenic according to our data. Variant chr7-6002590-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 9234.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-6002590-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7 linkuse as main transcript	c.400C>T	p.Arg134Ter	stop_gained	5/15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12 linkuse as main transcript	c.400C>T	p.Arg134Ter	stop_gained	5/15	1	NM_000535.7	ENSP00000265849	P3	P54278-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00000398

AC:

AN:

251140

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135722

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1459572

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

726102

show subpopulations

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:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

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:

0.00000756

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Lynch syndrome 4

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Sep 19, 2017	The c.400C>T (p.R134) variant in the PMS2 gene is predicted to introduce a premature translation stop codon. This variant has been reported in the literature in multiple individuals with constitutional mismatch repair deficiency syndrome as well as in individuals with colorectal cancer, Lynch syndrome and ovarian cancer (PMID: 15077197, 18602922, 23012243, 26681312, 26895986). The c.400C>T (p.R134) variant in the PMS2 gene is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 23, 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. -
Pathogenic, criteria provided, single submitter	research	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Dec 09, 2022	PVS1, PS3, PS4_STR, PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 22, 2017	- -

Lynch syndrome

Pathogenic:4

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 27, 2021	The p.Arg134X variant in PMS2 has been reported in at least 6 families (7 individuals) with PMS2-associated cancers (Parsons 1995 PMID: 7632227, Norquist 2016 PMID: 26720728, Rosty 2016 PMID: 26895986, LaDuca 2017 PMID: 28152038, Carter 2018 PMID: 30322717) and in the compound heterozygous state in 2 families (3 individuals) with constitutional mismatch repair disease (CMMRD; De Vos 2004 PMID: 15077197, Lavoine 2015 PMID: 26318770). It has also been identified in 1/128850 of European and 1/35440 of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 134, 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 vitro functional studies support an impact on protein function (Parsons 1995 PMID: 7632227, Nicolaides 1998 PMID: 9488480, Gibson 2006 PMID: 16426742). In addition, this variant was classified as pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (SCV000108365.2). 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, PS3_Moderate. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 13, 2018	Variant summary: PMS2 c.400C>T (p.Arg134X) 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 (eg. c.697C>T, p.Gln233X; c.736_741delinsTGTGTGTGAAG, p.Pro246fsX3). The variant allele was found at a frequency of 8.2e-06 in 121392 control chromosomes. c.400C>T has been reported in the literature in individuals affected with Turcot syndrome who carry a second pathogenic variant (DeVos_2004) and in patients with Lynch Syndrome and colorectal cancer (Senter_2008, Durno_2005). These data indicate that the variant is likely to be associated with disease. Additionally, this variant was found to have a dominant negative effect in hamster fibroblast cells (Nicolaides_1998) but not in human fibroblast cells (Yamada_2003). However, the variant was found to abrogate the interaction with MLH1 (Nicolaides_1998), a known pathogenic mechanism. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 22, 2024	This variant changes 1 nucleotide in exon 5 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-associated cancers (PMID: 18602922, 26720728, 26895986), and in an individual suspected of hereditary breast/ovarian cancer (PMID: 26270727). This variant has also been reported in individuals affected with constitutional mismatch repair deficiency (PMID: 7661930, 15077197, 15845562, 21376568, 26318770). This variant has been identified in 2/276892 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. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2023	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 the heterozygous state in individuals with a personal or family history consistent with pathogenic variants in this gene (Senter 2008, Vaughn 2013, Rosty 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17993636, 19495563, 26720728, 29922827, 31447099, 25525159, 7661930, 15845562, 16284300, 26318770, 26270727, 7632227, 18602922, 23012243, 9488480, 16283678, 21376568, 25850602, 12714694, 26895986, 28152038, 18709565, 15077197, 30322717, 32719484, 30787465, 33087929, 35449176, 36988593) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 09, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 19, 2023	This nonsense variant causes the premature termination of PMS2 protein synthesis. The frequency of this variant in the general population, 0.0000071 (2/282538 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with colorectal cancer (PMIDs: 26895986 (2016), 18602922 (2008)), Turcot syndrome (PMIDs: 15077197 (2004), 7661930 (1995)), ovarian cancer (PMIDs: 30322717 (2018), 26720728 (2016), 26681312 (2015)), and breast cancer (PMID: 35449176 (2022)). It has also been identified in individuals with CMMRD (PMIDs: 26318770 (2015), 25850602 (2015), 15077197 (2004)). Functional studies indicate this variant causes impaired DNA mismatch repair activity (PMIDs: 9488480 (1998), 7632227 (1995)). Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Aug 19, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 10, 2024	The p.R134* pathogenic mutation (also known as c.400C>T), located in coding exon 5 of the PMS2 gene, results from a C to T substitution at nucleotide position 400. This changes the amino acid from an arginine to a stop codon within coding exon 5. This alteration has been identified in multiple individuals with Constitutional Mismatch Repair Deficiency (CMMRD) syndrome caused by biallelic PMS2 mutations (Hamilton SR et al. N. Engl. J. Med. 1995 Mar;332:839-47; De Vos M et al. Am. J. Hum. Genet. 2004 May;74:954-64; Lavoine N et al. J. Med. Genet. 2015 Nov;52:770-8). This mutation has also been identified in multiple patients with Lynch syndrome-associated tumors that showed isolated loss of PMS2 protein expression on IHC (Senter L et al. Gastroenterology. 2008 Aug;135:419-28; Rosty C et al. BMJ Open. 2016 Feb;6:e010293). This alteration has also been detected in 1/1915 women with ovarian cancer, unselected for family history (Norquist BM et al. JAMA Oncol. 2016 Apr;2:482-90). 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 06, 2023	This variant changes 1 nucleotide in exon 5 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-associated cancers (PMID: 18602922, 26720728, 26895986), and in an individual suspected of hereditary breast/ovarian cancer (PMID: 26270727). This variant has also been reported in individuals affected with constitutional mismatch repair deficiency (PMID: 7661930, 15077197, 15845562, 21376568, 26318770). This variant has been identified in 2/276892 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. -

Mismatch repair cancer syndrome 4

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2004

- -

Lynch syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Apr 02, 2020

- -

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 18, 2024

This sequence change creates a premature translational stop signal (p.Arg134*) 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 (rs63750871, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with constitutional mismatch repair deficiency, colorectal cancer, Lynch syndrome, and ovarian cancer (PMID: 15077197, 18602922, 23012243, 25850602, 26318770, 26681312, 26895986). ClinVar contains an entry for this variant (Variation ID: 9234). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PMS2 function (PMID: 7632227, 9488480, 12714694). For these reasons, this variant has been classified as Pathogenic. -

Mismatch repair cancer syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Nov 13, 2019

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.97

MutationTaster

Benign

1.0

A;A;A;A;A

Vest4

0.94

GERP RS

5.8

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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