rs63750250

Positions:

• chr7-5986933-A-AT

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The ENST00000265849.12(PMS2):​c.1831_1832insA​(p.Ile611AsnfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,613,932 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. I611I) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: PMS2 ENST00000265849.12 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:27 O:2
• Conservation: PhyloP100: 1.22

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 7-5986933-A-AT is Pathogenic according to our data. Variant chr7-5986933-A-AT is described in ClinVar as [Pathogenic]. Clinvar id is 91317.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7	c.1831_1832insA	p.Ile611AsnfsTer2	frameshift_variant	11/15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.1831_1832insA	p.Ile611AsnfsTer2	frameshift_variant	11/15	1	NM_000535.7	ENSP00000265849	P3

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152054 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251456 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135920

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: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.0000206 AC XY: 15 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000243

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152054 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74270

Gnomad4 AFR AF: 0.00

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: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000489 Hom.: 0

Bravo AF: 0.0000378

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:27 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome Pathogenic:7 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 29, 2016	Variant summary: The PMS2 c.1831dupA (p.Ile611Asnfs) variant results in a premature termination codon, predicted to cause a truncated or absent PMS2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Mutation taster predicts a damaging outcome for this variant. This variant was found in 1/121354 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). It was reported in several cancer patients whose tumor had high MSI and lack of PMS2 staining based on IHC indicating pathogenicity. Additionally, truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Gln637fs) suggesting the clinical importance of the C-termial region located downstream of the variant. Moreover, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.1831dup;p.(Ile611Asnfs*2) is a null frameshift variant (NMD) in the PMS2 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevantexon to the transcript -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 91317; PMID: 23012243; 25512458; 25980754; 15887099; 18602922; 22577899; 20205264; 24728189) - PS4. This variant is not present in population databases (rs63750250, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 03, 2024	This variant inserts 1 nucleotide in exon 11 of the PMS2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 1828insA, 1831insA and c.1831_1832insA in the literature. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected by/suspected of having Lynch syndrome (PMID: 18602922, 20205264, 22120844, 24728189, 25512458, 25856668, 26681312), in individuals affected by/suspected of having recessive constitutional DNA mismatch repair deficiency (CMMRD) syndrome (PMID: 26116798, 27017610, 27037742, 28562508, 32773772), and in a compound heterozygous individual affected with invasive adenocarcinoma (PMID: 30155321). This variant has been identified in 6/282838 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 19, 2019	The p.Ile611AsnfsX2 variant in PMS2 has been reported in 12 individuals with colorectal cancer including 10 with Lynch Syndrome (Bodo 2015, ten Broeke 2015, Lavoine 2015, Goodenberger 2016, Susswein 2016), as well as in compound heterozygosity with another PMS2 variant in 2 individuals and 1 family member with constitutional MMR deficiency (Lavoine 2015, Bodo 2015, Susswein 2016). The p.Ile611AsnfsX2 variant has also been identified in 6/129170 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In addition, it has been classified as Pathogenic on September 5, 2013 by the InSiGHT expert panel (ClinVar SCV000108317.2). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 611 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of function of the PMS2 gene is an established disease mechanism in colorectal cancer. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP criteria applied: PM2,PS4_Moderate, PM3_Supporting, PVS1. -
Pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Sep 30, 2020	This is a frameshift alteration in which coding nucleotide 1831 is duplicated. This is predicted to change an Isoleucine to an Aparagine at amino acid codon 611, shift the reading frame and result in a premature stop codon 2 amino acids downstream. Classification crieria: PVS1, PS3, PM2. -

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 27, 2021	Frameshift 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 Lynch syndrome-related cancers and tumor studies consistent with pathogenic variants in this gene (Truninger 2005, Tomsic 2013, Vaughn 2013, Yurgelun 2015, Rosty 2016, van der Klift 2016, Wang 2020); Observed with a pathogenic variant on the opposite allele (in trans) and in the homozygous state in patients with Constitutional Mismatch Repair Deficiency in the published literature (Alexander 2016, Cheyuo 2017, Hildreth 2018, Oshrine 2019); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 1828insA; This variant is associated with the following publications: (PMID: 29625052, 31992580, 31447099, 27037742, 30155321, 31189528, 28562508, 15887099, 25980754, 23012243, 26895986, 27435373, 30322717, 26318770, 26116798, 28874130, 24728327, 28514183, 25512458, 26110232, 26681312, 27017610, 23652311, 24728189, 25691505, 25856668, 22120844, 22577899, 24362816, 20205264, 18602922) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 10, 2022	PP4, PP5, PM2, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 30, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 29, 2020	The PMS2 c.1831dup (p.Ile611Asnfs*2) variant alters the translational reading frame of the PMS2 mRNA and causes the premature termination of PMS2 protein synthesis. This variant has been reported in the published literature in several individuals and families affected with colorectal cancer (PMIDs: 15887099 (2005), 25980754 (2015), 27978560 (2016), 30155321 (2018)). The frequency of this variant in the general population, 0.000046 (6/129170 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Lynch syndrome 4 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Daryl Scott Lab, Baylor College of Medicine	Apr 11, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genetics Bochum, Ruhr University Bochum	Aug 03, 2023	ACMG criteria used to clasify this variant:PVS1, PS4, PM2_SUP -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Sep 13, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 21, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 22, 2024	- -

Hereditary cancer-predisposing syndrome Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	True Health Diagnostics	Oct 16, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 10, 2023	This variant inserts 1 nucleotide in exon 11 of the PMS2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 1828insA, 1831insA and c.1831_1832insA in the literature. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected by/suspected of having Lynch syndrome (PMID: 18602922, 20205264, 22120844, 24728189, 25512458, 25856668, 26681312), in individuals affected by/suspected of having recessive constitutional DNA mismatch repair deficiency (CMMRD) syndrome (PMID: 26116798, 27017610, 27037742, 28562508, 32773772), and in a compound heterozygous individual affected with invasive adenocarcinoma (PMID: 30155321). This variant has been identified in 6/282838 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. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Jun 11, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 09, 2021	The c.1831dupA pathogenic mutation, located in coding exon 11 of the PMS2 gene, results from a duplication of A at nucleotide position 1831, causing a translational frameshift with a predicted alternate stop codon (p.I611Nfs*2). This mutation has been reported in multiple individuals with Lynch syndrome-associated cancers, many with tumors demonstrating microsatellite instability and/or loss of PMS2 by immunohistochemistry (Truninger K et al. Gastroenterology, 2005 May;128:1160-71; Senter L et al. Gastroenterology, 2008 Aug;135:419-28; Schofield L et al. Fam Cancer, 2012 Mar;11:1-6; Vaughn CP et al. Genes Chromosomes Cancer, 2013 Jan;52:107-12; Pagin A et al. Br J Cancer, 2013 May;108:2079-87; Song H et al. Hum Mol Genet, 2014 Sep;23:4703-9; Bodo S et al. Gastroenterology, 2015 Oct;149:1017-29.e3; Susswein LR et al. Genet Med, 2016 08;18:823-32; van der Klift HM et al. Hum Mutat, 2016 11;37:1162-1179; Cheyuo C et al. J. Pediatr. Hematol. Oncol., 2017 10;39:e381-e387; Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471; Rossi BM et al. BMC Cancer, 2017 Sep;17:623; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Wang Q et al. J Med Genet, 2020 07;57:487-499; Post CCB et al. J Natl Cancer Inst, 2021 Mar). In addition, this mutation has been identified as homozygous and in trans with additional PMS2 alterations in patients with constitutional mismatch repair deficiency (CMMRD) phenotypes (Lavoine N et al. J. Med. Genet. 2015 Nov;52:770-8; Alexander TB et al. Pediatr. Blood Cancer. 2016 Aug;63:1454-6; Mork ME et al. Fam. Cancer. 2016 Oct;15:587-91; Hildreth A et al. Case Rep. Genet. 2018 Jul;2018:8657823; Shuen AY et al. J Clin Oncol, 2019 02;37:461-470; Perez-Valencia JA et al. Genet Med, 2020 12;22:2081-2088; Oldfield LE et al. J Mol Diagn, 2021 02;23:242-252). This alteration has also been reported in 3/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). Of note, this alteration is also designated as 1828insA, c.1831_1832insA and 1831dup in published literature. 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. -

Lynch syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Pathway Genomics

Jul 24, 2014

- -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

This sequence change creates a premature translational stop signal (p.Ile611Asnfs*2) 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 (rs63750250, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with colorectal cancer and constitutional mismatch repair deficiency syndrome and Lynch syndrome or suspected Lynch syndrome and ovarian cancer (PMID: 15887099, 18602922, 20205264, 22577899, 23012243, 24728189, 25512458, 25980754, 26318770). This variant is also known as 1828insA, 1831insA, and 1831_1832insA. ClinVar contains an entry for this variant (Variation ID: 91317). 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.1831dupA, was found in compound heterozygosity with the pathogenic variant NM_000535.6:c.(988+1_989-1)_(1144+1_1145-1)del. Sample UAB117 in Perez J et al, Genet Med (PMID: 32773772). -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

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: rs63750250; hg19: chr7-6026564;