rs587781626

chr7-5973486-CAT-CC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_000535.7(PMS2):c.2500_2501delinsG(p.Met834GlyfsTer17) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 9)
• Consequence: PMS2 NM_000535.7 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.32

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 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 16 pathogenic variants in the truncated region.
• PP5: Variant 7-5973487-AT-C is Pathogenic according to our data. Variant chr7-5973487-AT-C is described in ClinVar as [Pathogenic]. Clinvar id is 141280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.2500_2501delinsG	p.Met834GlyfsTer17	frameshift_variant	15/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.2500_2501delinsG	p.Met834GlyfsTer17	frameshift_variant	15/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes Cov.: 9

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 9

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 19, 2023	This variant alters 2 nucleotides in exon 15 of the PMS2 gene, creating a frameshift at codon 834 and a premature stop at codon 850. While this variant is not expected to trigger nonsense-mediated decay, a truncated C-terminal polypeptide (lacking a.a. 826-850) has previously been shown to lack binding to MLH1 (PMID: 10037723) and single missense mutations in codons 843, 845 and 847 have been shown to disrupt DNA mismatch repair in vitro (PMID: 18619468). This variant is expected to result in a non-functional protein product. This variant has been reported in multiple individuals affected with Lynch syndrome-associated cancer (PMID: 23012243, 25856668, 28514183, 30322717). Moreover, further C-terminal truncation at codon 836 and a frameshift at codon 841 have been observed in an individual suspected of Lynch syndrome (PMID: 28514183) and individuals affected with biallelic constitutional mismatch repair deficiency syndrome (PMID: 26116798, 30764633), respectively. 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 Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 01, 2022	The c.2500_2501delATinsG pathogenic mutation, located in coding exon 15 of the PMS2 gene, results from the deletion of two nucleotides and insertion of one nucleotide causing a translational frameshift with a predicted alternate stop codon (p.M834Gfs*17). This alteration occurs at the 3' terminus of thePMS2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 29 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This mutation has been reported in individuals with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome, including multiple probands whose Lynch syndrome-associated tumors demonstrated loss of PMS2 expression by immunohistochemistry (Espenschied CR et al. J Clin Oncol, 2017 Aug;35:2568-2575; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Roberts ME et al. Genet Med, 2018 10;20:1167-1174; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PMS2 p.Met834Glyfs*17 variant was identified in 3 of 69960 proband chromosomes (frequency: 0.00004) from individuals or families with Lynch Syndrome (Espenschied 2017). The variant was also identified in ClinVar (classified as pathogenic by Ambry Genetics, Invitae), Clinvitae (classified as pathogenic by ClinVar), Insight Hereditary Tumors Database, databases. The variant was not identified in dbSNP, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, databases. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The c.2500_2501delinsG variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 834 and leads to a premature stop codon at position 850. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the PMS2 gene are an established mechanism of disease in Lynch Syndrome 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

Nov 14, 2022

Variant summary: PMS2 c.2500_2501delinsG (p.Met834GlyfsX17) 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 likely pathogenic by our laboratory. The variant was absent in 145224 control chromosomes (gnomAD). c.2500_2501delinsG has been reported in the literature in individuals affected with Lynch Syndrome and associated cancers (Carter_2018, Espenschied_2017, Goodenberger_2015, LaDuca_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions (evaluation after 2014) cite this variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Aug 05, 2018

- -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 05, 2024

This sequence change creates a premature translational stop signal (p.Met834Glyfs*17) in the PMS2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acid(s) of the PMS2 protein. The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This premature translational stop signal has been observed in individual(s) with clinical features of constitutional mismatch repair deficiency syndrome (CMMR-D) and/or clinical features of Lynch syndrome (PMID: 23012243, 25856668, 28514183, 30322717; Scientific presentation). 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: 141280). This variant disrupts the MLH1 interaction domain of the PMS2 protein, which has been shown to be critical for PMS2-MLH1 dimerization (PMID: 10037723), and therefore mismatch repair activity (PMID: 16338176, 20533529). While functional studies have not been performed to directly test the effect of this variant on PMS2 protein function, this suggests that disruption of this region of the protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. -

Lynch syndrome 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Sep 25, 2023

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

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: rs587781626; hg19: chr7-6013118;