NM_000535.7:c.1239dupA

Variant names:

• chr7-5987525-C-CT
• rs267608159
• NM_000535.7:c.1239dupA

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.1239dupA​(p.Asp414ArgfsTer44) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. K413K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PMS2 NM_000535.7 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:17
• Conservation: PhyloP100: 0.163
• Publications: 14 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 7-5987525-C-CT is Pathogenic according to our data. Variant chr7-5987525-C-CT is described in ClinVar as Pathogenic. ClinVar VariationId is 216072.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.1239dupA	p.Asp414ArgfsTer44	frameshift_variant	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.1239dupA	p.Asp414ArgfsTer44	frameshift_variant	Exon 11 of 15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000479 AC: 7 AN: 1461794 Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4 AN XY: 727204

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: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

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

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111928

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Nov 08, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PMS2 c.1239dup (p.Asp414Argfs*44) variant alters the translational reading frame of the PMS2 mRNA and causes the premature termination of PMS2 protein synthesis. In the published literature, this variant has been reported in individuals with breast cancer (PMID: 37239058 (2023)), Lynch syndrome (PMIDs: 28874130 (2017), 26437257 (2015)), and CMMRD syndrome (PMID: 20205264 (2010)). The frequency of this variant in the general population, 0.000032 (1/31348 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 06, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This duplication of one nucleotide in PMS2 is denoted c.1239dupA at the cDNA level and p.Asp414ArgfsX44 (D414RfsX44) at the protein level. The normal sequence, with the base that is duplicated in brackets, is GAAAAAAA[dupA]GACG. The duplication causes a frameshift which changes an Aspartic Acid to an Arginine at codon 414, and creates a premature stop codon at position 44 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. PMS2 c.1239dupA has been observed in the compound heterozygous state with a nonsense variant in an individual with brain cancer and duodenal cancer diagnosed prior to age 18, consistent with autosomal recessive constitutional mismatch repair deficiency syndrome (Vaughn 2010). This variant was also observed in an individual with early-onset colon cancer and family history meeting Amsterdam Criteria I (Carneiro da Silva 2015). We consider this variant to be pathogenic. -

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PMS2: PVS1, PM2, PS4:Moderate -

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Sep 13, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1239dupA pathogenic mutation, located in coding exon 11 of the PMS2 gene, results from a duplication of A at nucleotide position 1239, causing a translational frameshift with a predicted alternate stop codon (p.D414Rfs*44). This alteration was detected in conjunction with PMS2 c.1927C>T (p.Gln643X) in a patient diagnosed with a brain tumor at age 14 and a PMS2-deficient duodenal tumor at age 15, which is consistent with a diagnosis of constitutional mismatch repair deficiency syndrome; further, this patient's mother's testing detected the c.1239dupA alteration only (Vaughn CP et al. Hum. Mutat. 2010 May;31:588-93). In a study of Brazilian patients suspected to have Lynch syndrome, this alteration was reported in a patient with colon cancer at age 37, whose family history met Amsterdam I Criteria (Carneiro da Silva F et al. PLoS ONE. 2015 Oct;10:e0139753). 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. -

Jan 01, 2020

GeneKor MSA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant consists of 1 nucleotide insertion in exon 11 of the PMS2 mRNA (c.1239dupA), causing a frameshift at codon 414. Consequently, a premature stop codon is created 44 amino acid residues later. This is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMS2 are known to be pathogenic. This variant has been described in the international literature (PMID: 26437257, PMID: 20205264). The mutation database ClinVar contains entries for this variant (Variation ID: 216072/). -

Apr 05, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant inserts 1 nucleotide in exon 11 of the PMS2 gene, creating a frameshift and premature translation stop signal. 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 an individual suspected of Lynch syndrome (PMID: 26437257). This variant has also been reported in individuals affected with or suspected of constitutional mismatch repair syndrome (PMID: 20205264, 21261604, 25691505). This variant has been identified in 1/31348 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:2

-

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

A known single nucleotide duplication, c.1239dup in exon 11 of the PMS2 was identified in the homozygous state in the proband (Li et al., 2015; Vaughn et al., 2010). Segregation analysis using Sanger sequencing showed that the variant was present heterozygous state in the parents. This variant was observed in seven individuals in the heterozygous state and absent in homozygous state in gnomAD (v4.1.0). This variant is absent in our in-house database of 3412 exomes. This variant results in premature stop codon which can either cause the transcript to undergo nonsense-mediated mRNA decay or lead to formation of a truncated protein product. -

Nov 29, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome 4 Pathogenic:2

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 frameshift predicted to result in premature protein truncation. -

Jul 20, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PMS2-related disorder Pathogenic:1

Apr 09, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PMS2 c.1239dupA variant is predicted to result in a frameshift and premature protein termination (p.Asp414Argfs*44). This variant has been previously reported in individuals with non-polyposis colorectal cancer/Lynch syndrome (Carneiro da Silva et al. 2015. PubMed ID: 26437257; Rossi et al. 2017. PubMed ID: 28874130; Table S2-Tsaousis et al. 2019. PubMed ID: 31159747; Vaughn et al. 2010. PubMed ID: 20205264). This variant is reported in 0.011% of alleles in individuals of African descent in gnomAD. Frameshift variants in PMS2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Hereditary nonpolyposis colon cancer Pathogenic:1

Jan 05, 2024

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.1239dupA (p.Asp414ArgfsX44) 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. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.1239dupA has been reported in the literature in individuals affected with suspected Lynch Syndrome (e.g., Carneiro da Silva_2015). The following publication was ascertained in the context of this evaluation (PMID: 26437257). ClinVar contains an entry for this variant (Variation ID: 216072). Based on the evidence outlined above, the variant was classified as pathogenic. -

Lynch syndrome Pathogenic:1

Mar 25, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant inserts 1 nucleotide in exon 11 of the PMS2 gene, creating a frameshift and premature translation stop signal. 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 an individual suspected of having Lynch syndrome (PMID: 26437257). This variant has been reported in individuals affected or suspected of having constitutional mismatch repair syndrome (PMID: 20205264, 21261604, 25691505)This variant has been identified in 1/31348 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. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Dec 04, 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.Asp414Argfs*44) 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 (no rsID available, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with constitutional mismatch repair deficiency-associated tumors (PMID: 20205264, 25691505, 26437257). 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: 216072). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.16
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs267608159; hg19: chr7-6027156; COSMIC: COSV56222171;