rs863224676

Variant names:

• chr7-6005923-TTCTACTAAC-T
• rs863224676
• NM_000535.7:c.123_131delGTTAGTAGA

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PM4 PP3 PP5_Very_Strong

The NM_000535.7(PMS2):​c.123_131delGTTAGTAGA​(p.Leu42_Glu44del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,556 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E41E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PMS2 NM_000535.7 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 U:1
• Conservation: PhyloP100: 8.91
• Publications: 3 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 15 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 50 uncertain in NM_000535.7
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000535.7.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 7-6005923-TTCTACTAAC-T is Pathogenic according to our data. Variant chr7-6005923-TTCTACTAAC-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 216449.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.123_131delGTTAGTAGA	p.Leu42_Glu44del	disruptive_inframe_deletion	Exon 2 of 15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.123_131delGTTAGTAGA	p.Leu42_Glu44del	disruptive_inframe_deletion	Exon 2 of 15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 245774 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458556 Hom.: 0 AF XY: 0.00000276 AC XY: 2 AN XY: 725602

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33406

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111822

Other (OTH) AF: 0.00 AC: 0 AN: 60194

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lynch syndrome 4 Pathogenic:2 Uncertain:1

Feb 27, 2025

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 13, 2018

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Feb 02, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome Pathogenic:2

Jul 29, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is a 3 amino acid deletion within the amino-terminal ATPase domain of the PMS2 protein. Functional studies have shown that this variant is defective for protein expression, mismatch repair activity and ATPase activity, and demonstrated increased microsatellite instability (PMID: 30653781, 35189042). Structural studies have also indicated the variant protein is disordered and prone to aggregation (PMID: 30653781). This variant has been reported in several individuals affected with Lynch syndrome-associated cancers (PMID: 25980754; ClinVar SCV000254595.11, SCV000663563.5). This variant has also been observed in compound heterozygous state with a known pathogenic PMS2 variant in an individual affected with autosomal recessive constitutional mismatch repair disorder (PMID: 30653781). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Oct 14, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Leu42_Glu44del variant in MSH6 has been reported in 1 individual with suspected diagnosis of Lynch syndrome who also carried a variant of uncertain significance in ATM (Yurgelun 2015) and in an individual with constitutive mismatch repair deficiency in the compound heterozygous state (D'Arcy 2019). This variant has also been reported in ClinVar (ClinVar ID 216449), with conflicting interpretations. It was absent from large population studies. This variant is a deletion of 3 amino acids at position 42 and is not predicted to alter the protein reading-frame. In vitro functional studies provide some evidence that this variant impacts protein function (D'Arcy 2019); however, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PM2, PM3, PM4, PS3_Supporting. -

not provided Pathogenic:2

Mar 05, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PMS2 c.123_131del (p.Leu42_Glu44del) variant has been reported in the published literature in individuals with constitutive mismatch repair deficiency syndrome (CMMRD) and suspected Lynch syndrome (PMIDs: 25980754 (2015), 30653781 (2020)). In functional studies, this variant was shown to cause a damaging effect on gene function and protein structure (PMID: 30653781 (2020)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as likely pathogenic. -

Jul 03, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with Lynch-associated cancer and/or polyps (PMID: 25980754); Published functional studies demonstrate a damaging effect: deficient mismatch repair activity, reduced protein expression, and absent ATPase activity (PMID: 30653781); In-frame deletion of 3 amino acids in a non-repeat region predicted to critically alter the protein.; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30653781, 32719484, 25980754) -

Hereditary cancer-predisposing syndrome Pathogenic:2

May 08, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is a 3 amino acid deletion within the amino-terminal ATPase domain of the PMS2 protein. Functional studies have shown that this variant is defective for protein expression, mismatch repair activity and ATPase activity, and demonstrated increased microsatellite instability (PMID: 30653781, 35189042). Structural studies have also indicated the variant protein is disordered and prone to aggregation (PMID: 30653781). This variant has been reported in several individuals affected with Lynch syndrome-associated cancers (PMID: 25980754; ClinVar SCV000254595.11, SCV000663563.5). This variant has also been observed in compound heterozygous state with a known pathogenic PMS2 variant in an individual affected with autosomal recessive constitutional mismatch repair disorder (PMID: 30653781). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Sep 06, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.123_131delGTTAGTAGA pathogenic mutation (also known as p.L42_E44del) is located in coding exon 2 of the PMS2 gene. This variant results from an in-frame deletion of 9 nucleotides at positions 123 to 131. This results in the deletion of three amino acids between codons 42 and 44. This alteration has been identified in three unrelated individuals with colorectal tumors that demonstrated isolated loss of PMS2 expression by IHC; two of these probands had a family history of colorectal cancer (Ambry internal data). This variant has been reported in a cohort of healthy individuals undergoing population screening for genetic conditions (Grzymski JJ et al. Nature Med. 2020 Aug;26(8):1235-9). However, it was also identified in a patient with Constitutional Mismatch Repair Deficiency syndrome (CMMRD), who also had PMS2 mutation p.R802* in trans, and functional analysis demonstrated that this variant lacks in vitro mismatch repair and ATPase activities (D'Arcy BM et al. Hum. Mutat. 2019 Apr;40:458-471). Based on an internal structural assessment, this alteration disrupts critical ATP-binding residues (Ban C et al. Cell. 1999 Apr;97:85-97; Guarné A et al. EMBO J. 2001 Oct;20:5521-31; Wu H et al. Acta Crystallogr F Struct Biol Commun. 2015 Aug;71:981-5). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). These amino acid positions are well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012;7:e46688). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary nonpolyposis colon cancer Pathogenic:1

Apr 22, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PMS2 c.123_131delGTTAGTAGA (p.Leu42_Glu44del) results in an in-frame deletion that is predicted to remove three amino acids from the encoded protein. The variant allele was found at a frequency of 1.4e-06 in 1458556 control chromosomes (gnomAD v4.1). c.123_131delGTTAGTAGA has been reported in the literature in one individual who had a history of Lynch syndrome associated cancer and/or polyps (Yurgelun_2015). D'Arcy_2019 reported this variant an individual who was clinically diagnosed with constitutive mismatch repair deficiency syndrome (CMMRD) and was compound heterozygous with a pathogenic variant. These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant ablated MMR capacity and ATPase activity (D'Arcy_2019). The following publications have been ascertained in the context of this evaluation (PMID: 25980754, 30653781). ClinVar contains an entry for this variant (Variation ID: 216449). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Jan 16, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.123_131del, results in the deletion of 3 amino acid(s) of the PMS2 protein (p.Leu42_Glu44del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Lynch syndrome and constitutive mismatch repair deficiency syndrome (PMID: 25980754, 30653781; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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: 216449). 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 have shown that this variant affects PMS2 function (PMID: 30653781). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.9

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs863224676; hg19: chr7-6045554;