rs63750871

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong

The NM_001322009.2(PMS2):c.-6C>T variant causes a 5 prime UTR premature start codon gain 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 (★★★).

Frequency

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

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

PMS2
NM_001322009.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:21

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 12 ACMG points.

PP3

BayesDel_addAF computational evidence supports a deleterious effect, 0.62

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 rank	MANE	Protein	UniProt
PMS2	NM_000535.7 link	c.400C>T	p.Arg134*	stop_gained	Exon 5 of 15	ENST00000265849.12	NP_000526.2	P54278-1Q7Z3Q2B4DGM0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12 link	c.400C>T	p.Arg134*	stop_gained	Exon 5 of 15	1	NM_000535.7	ENSP00000265849.7		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:21

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Lynch syndrome 4

Pathogenic:5

May 22, 2017

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 23, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 05, 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. -

Dec 09, 2022

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PVS1, PS3, PS4_STR, PM2_SUP -

Sep 19, 2017

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Lynch syndrome

Pathogenic:4

Jul 13, 2018

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.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. -

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 28, 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 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. -

Oct 27, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided

Pathogenic:3

Jan 19, 2023

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, 0.0000071 (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. -

Jul 07, 2023

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; 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) -

Sep 09, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:3

May 10, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 06, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 19, 2021

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Mismatch repair cancer syndrome 4

Pathogenic:1

May 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Lynch syndrome 1

Pathogenic:1

Apr 02, 2020

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gastric cancer

Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Lynch syndrome 4;C5436817:Mismatch repair cancer syndrome 4

Pathogenic:1

Mar 02, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms

Pathogenic:1

Nov 24, 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.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). 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: 9234). Algorithms developed to predict the effect of variants on gene product 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

Nov 13, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

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