rs863224676

Positions:

• chr7-6005923-TTCTACTAAC-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM4 PP3 PP5

The NM_000535.7(PMS2):​c.123_131del​(p.Leu42_Glu44del) variant causes a 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 Conflicting classifications of pathogenicity (no stars). 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 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:1
• Conservation: PhyloP100: 8.91

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 216449.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Pathogenic=4, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.123_131del	p.Leu42_Glu44del	inframe_deletion	2/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.123_131del	p.Leu42_Glu44del	inframe_deletion	2/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes Cov.: 32

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

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lynch syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 14, 2019	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Apr 10, 2023	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 accession: SCV000663563.3). 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. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 23, 2023	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 SCV000663563.3). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 17, 2021	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). 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 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 (D'Arcy BM et al. Hum. Mutat. 2019 Apr;40:458-471). D'Arcy et al. also demonstrated that this variant lacks in vitro mismatch repair and ATPase activities. These amino acid positions are well conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Lynch syndrome 4 Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 13, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 02, 2024	- -

Hereditary nonpolyposis colon cancer Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Apr 22, 2024

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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 10, 2020

In-frame deletion of 3 amino acids in a non-repeat region predicted to critically alter the protein.; Published functional studies demonstrate a damaging effect: deficient mismatch repair activity, reduced protein expression, and absent ATPase activity (DArcy 2019); Observed in individuals with Lynch-associated cancer and/or polyps (Yurgelun 2015); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30653781, 25980754, 32719484) -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 08, 2023

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; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 216449). Algorithms developed to predict the effect of variants on protein 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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs863224676; hg19: chr7-6045554;