rs587778618

Variant names:

• chr7-5987078-G-A
• rs587778618
• NM_000535.7:c.1687C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-5987078-G-A
• chr7-5987078-G-C
• chr7-5987078-G-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000535.7(PMS2):​c.1687C>T​(p.Arg563*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R563R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PMS2 NM_000535.7 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:16 O:1
• Conservation: PhyloP100: 0.466
• Publications: 30 publications found

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 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Lynch syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• mismatch repair cancer syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• ovarian cancer

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• Muir-Torre syndrome

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 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 7-5987078-G-A is Pathogenic according to our data. Variant chr7-5987078-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 135067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7	c.1687C>T	p.Arg563*	stop_gained	Exon 11 of 15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.1687C>T	p.Arg563*	stop_gained	Exon 11 of 15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251330 AF XY: 0.00

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000342 AC: 5 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727236

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000467 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:4

Mar 23, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2_Supporting, PM3, PP4_Strong c.1687C>T, located in exon 11 of the PMS2 gene, is a nonsense variant expected to result in loss of function by premature protein truncation and nonsense-mediated mRNA decay (PVS1). This variant is found in 5/1614120 alleles at a frequency of 0,0003% in the gnomAD v4 database (PM2_Supporting). The SpliceAI algorithm predicts no significant impact on splicing. To our knowledge, no well-established functional studies have been reported for this variant. It has been reported in a homozygous state in CMMRD-suspected patients (PMID: 27082517, 20205264), as well as in a confirmed CMMRD patient with another PMS2 pathogenic variant in trans (PMID: 22608206) (PM3). It has been identified in multiple CRC-affected patients with isolated loss of PMS2 by IHC (PMID: 31992580, 25856668, and data from our internal cohort of patients) (PP4_Strong). This variant has been reported in the ClinVar database (14x pathogenic), in the LOVD database (2x pathogenic, 1x likely pathogenic) and has not been classified by InSiGHT. Based on currently available information, the variant c.1687C>T should be considered a pathogenic variant according to ClinGen CRC ACMG Specifications PMS2 v1.0.0. -

Jun 12, 2024

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 been reported in individuals affected with Lynch syndrome (PMID: 31992580), breast and/or ovarian cancer (31512090, 31650731), and colorectal cancer (PMID: 25856668, 29478780, 31857677). This variant has also been reported in compound heterozygous individuals affected with constitutional mismatch repair deficiency (PMID: 21618646, 22608206). This variant has been identified in 2/251330 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. -

Mar 01, 2021

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

May 20, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1687C>T (p.R563*) alteration, located in exon 11 (coding exon 11) of the PMS2 gene, consists of a C to T substitution at nucleotide position 1687. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 563. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.001% (2/251330) total alleles studied. The highest observed frequency was 0.012% (2/16190) of African alleles. This variant has been detected in an individual diagnosed with a brain tumor at the age of 8 and demonstrated a neurofibromatosis type 1 phenotype; this patient was also identified to carry a PMS2 exon 15 deletion (Vaughn, 2010; Vaughn, 2011). This variant has also been detected in trans with a gross PMS2 deletion involving exons 12 through 14 in a 13-year-old patient diagnosed with rectal cancer and two cafe-au-lait spots, a phenotype consistent with CMMR-D (Vasovcak, 2012). This variant was also reported in the homozygous state in a pediatric patient with a personal history of AML and osteosarcoma (Ortiz, 2016). Additionally, this variant has been reported in several individuals with early-onset colorectal cancer whose tumors demonstrated absent PMS2 protein staining on immunohistochemistry (Goodenberger, 2016; Wang, 2020). Based on the available evidence, this alteration is classified as pathogenic. -

not provided Pathogenic:3

Sep 14, 2020

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. In the published literature, this variant has been reported in individuals with lynch syndrome whose tumors showed loss of PMS protein in Immunohistochemistry assays (PMID: 31992580 (2020)). In addition, this variant has been detected in individuals affected with other cancers including colorectal, breast and/or ovarian, endometrial, kidney and brain cancers (PMIDs: 31857677 (2020), 31650731 (2020), 31512090 (2019), 31336956 (2019), 30103829 (2018), 29478780 (2018), 27376475 (2016), 25194673 (2014), and 20205264 (2010). Also, this variant has been reported in individuals with phenotypes consistent with autosomal recessive constitutional mismatch repair deficiency (CMMR-D) syndrome (PMIDs: 22608206 (2012) and 21618646 (2011)). Based on the available information, this variant is classified as pathogenic. -

Jan 27, 2021

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 individuals with a personal or family history consistent with pathogenic variants in this gene and in a child with personal history suspicious for CMMR-D without a second identifiable PMS2 pathogenic variant (Vaughn 2010, Goodenberger 2016, AlDubayan 2018, Wang 2020); Observed with a pathogenic variant on the opposite allele (in trans) and in the apparent homozygous state in individuals with personal histories consistent with Constitutional Mismatch Repair Deficiency in the published literature (Vasovcak 2012, Ortiz 2016); 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: 28502729, 29625052, 26689913, 24728327, 25525159, 20205264, 26648449, 27742654, 28281021, 29478780, 30217226, 25856668, 27082517, 22608206, 31992580, 31512090, 31650731, 31857677, 30787465) -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PMS2: PVS1, PM2, PS4:Moderate -

Lynch syndrome 4 Pathogenic:3

Oct 08, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

Feb 13, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Carcinoma of colon Pathogenic:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PMS2 p.Arg563X variant was identified in 5 of 818 proband chromosomes (frequency: 0.006) from individuals or families with Lynch Syndrome, colorectal cancer, endometrial cancer, and biallelic mismatch repair deficiency (Goodenberger 2016, Haraldsdottir 2014, Jansen 2016, Vaughn 2010, Vasovcak 2012). The variant was also identified in the following databases: dbSNP (ID: rs587778618) as "With Pathogenic, Uncertain significance allele", ClinVar (3x, pathogenic), Clinvitae (2x, pathogenic), and Cosmic (3x, confirmed somatic, in carcinomas of the skin and lung). The variant was not identified in MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was also identified by our laboratory in one individual with a family history of Lynch Syndrome. The variant was identified in control databases in 2 of 246126 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 2 of 15246 chromosomes (freq: 0.0001). The variant was not observed in the other, Latino, European, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The c.1687C>T variant leads to a premature stop codon at position 563, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PMS2 gene are an established mechanism of disease and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

PMS2-related disorder Pathogenic:1

Sep 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PMS2 c.1687C>T variant is predicted to result in premature protein termination (p.Arg563*). This variant has previously been reported to be causative for colorectal cancer, male breast cancer, constitutional mismatch repair deficiency syndrome and Lynch syndrome (Table S6, AlDubayan et al. 2018. PubMed ID: 29478780; Scarpitta et al. 2019. PubMed ID: 31512090; Vaughn et al. 2010. PubMed ID: 20205264; Vasovcak et al. 2012. PubMed ID: 22608206; Wang et al. 2020. PubMed ID: 31992580; Table S1, Goodenberger et al. 2016. PubMed ID: 25856668). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/135067/). Nonsense variants in PMS2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Hereditary nonpolyposis colon cancer Pathogenic:1

Feb 27, 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.1687C>T (p.Arg563X) 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 8e-06 in 251330 control chromosomes (gnomAD). c.1687C>T has been reported in the literature in multiple individuals affected with colorectal cancer, and phenotypes consistent with autosomal recessive constitutional mismatch repair deficiency (CMMR-D) syndrome (example: Vaughn_2010, Vasovcak_2012, Goodenberger_2015, and Wang_2020). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Lynch syndrome Pathogenic:1

Mar 28, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1687C>T variant in the PMS2 gene is located on the exon 11 and introduces a premature translation termination codon (p.Arg563*), resulting in an absent or disrupted protein product. This variant has been reported in multiple individuals with Lynch syndrome; colorectal cancer (PMID: 31992580, 31650731, 28514183, 29345684); breast cancer, and endometrial cancer (PMID: 29345684, 31650731, 34994648). This variant has also been reported in compound heterozygosity in an individual with constitutional mismatch repair deficiency syndrome (PMID: 22608206). Loss-of-function variants in PMS2 gene are known to be pathogenic (PMID: 28514183, 25512458, 35223509). The variant is reported in ClinVar (ID: 135067). The variant is rare in general population database according to gnomAD (2/251330 chromosomes). Therefore, the c.1687C>T (p.Arg563*) variant in PMS2 gene has been classified as pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Dec 18, 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.Arg563*) 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 (rs587778618, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with colorectal cancer, breast cancer and phenotypes consistent with autosomal recessive constitutional mismatch repair deficiency (CMMR-D) syndrome (PMID: 20205264, 22608206, 25856668). 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: 135067). For these reasons, this variant has been classified as Pathogenic. -

Lynch syndrome 4;C5436817:Mismatch repair cancer syndrome 4 Pathogenic:1

Jan 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	33
DANN	Benign	0.96
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.12	N
PhyloP100		0.47
Vest4		0.78
GERP RS		-5.0
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587778618; hg19: chr7-6026709; COSMIC: COSV56221094;