rs587778618

Positions:

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

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000535.7(PMS2):​c.1687C>T​(p.Arg563Ter) 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:13 O:1
• Conservation: PhyloP100: 0.466

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 Pathogenic. Variant got 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 id is 135067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5987078-G-A is described in Lovd as [Likely_pathogenic]. Variant chr7-5987078-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.1687C>T	p.Arg563Ter	stop_gained	11/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.1687C>T	p.Arg563Ter	stop_gained	11/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251330 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135868

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

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000279 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 15, 2021	The p.R563* pathogenic mutation (also known as c.1687C>T), located in coding exon 11 of the PMS2 gene, results from a C to T substitution at nucleotide position 1687. This changes the amino acid from an arginine to a stop codon within coding exon 11. This alteration 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 CP et al. Hum. Mutat. 2010 May;31:588-93; Vaughn CP et al. Hum Mutat. 2011 Sep;32:1063-71). This mutation 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 P et al. DNA Repair (Amst.). 2012 Jul;11:616-23). This alteration was also reported in the homozygous state in a pediatric patient with a personal history of AML and osteosarcoma (Ortiz MV et al. Pediatr Blood Cancer. 2016 08;63:1368-74). Additionally, this alteration has been reported in several individuals with early-onset colorectal cancer whose tumors demonstrated absent PMS2 protein staining on immunohistochemistry (Goodenberger ML et al. Genet Med. 2016 Jan;18:13-9; Wang Q et al. J Med Genet. 2020 07;57:487-499). 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	curation	Sema4, Sema4	Mar 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 09, 2023	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. -

Lynch syndrome 4 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Oct 08, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 20, 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	clinical testing	Baylor Genetics	Feb 13, 2024	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 14, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 27, 2021	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) -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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. -

Hereditary nonpolyposis colon cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Feb 27, 2023

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

Pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Dec 18, 2023

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

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). 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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 14, 2022

- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

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
MutationTaster	Benign	1.0	A;A;A;N;N
Vest4		0.78
GERP RS		-5.0

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