rs587782710

Variant names:

• chr7-5997375-ACACGGAGT-A
• rs587782710
• NM_000535.7:c.746_753delACTCCGTG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000535.7(PMS2):​c.746_753delACTCCGTG​(p.Asp249ValfsTer2) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,526 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PMS2 NM_000535.7 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 7.77

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 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 7-5997375-ACACGGAGT-A is Pathogenic according to our data. Variant chr7-5997375-ACACGGAGT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 142778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5997375-ACACGGAGT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7	c.746_753delACTCCGTG	p.Asp249ValfsTer2	frameshift_variant	Exon 7 of 15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.746_753delACTCCGTG	p.Asp249ValfsTer2	frameshift_variant	Exon 7 of 15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456526 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 725000

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

May 12, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; Not observed at significant frequency in large population cohorts (gnomAD); Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Talseth-Palmer et al., 2010; Yurgelun et al., 2015; Goodenberger et al., 2016; Wang et al., 2020); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 20487569, 25856668, 27064304, 28514183, 27435373, 30787465, 31992580, 25980754) -

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Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PMS2 p.Asp249Valfs*2 variant was identified in 3 of 3382 proband chromosomes (frequency: 0.0009) from individuals or families with Lynch syndrome (Talseth-Palmer 2016, van der Klift 2016, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs587782710) as “With Pathogenic allele”, ClinVar and Clinvitae (as pathogenic by Ambry Genetics and Invitae), and Insight Hereditary Tumors Database (4x). The variant was not identified in COGR, Cosmic, MutDB, Zhejiang Colon Cancer Database, or the Mismatch Repair Genes Variant Database. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.746_753del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 249 and leads to a premature stop codon at position 250. 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. -

Sep 24, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Hereditary cancer-predisposing syndrome Pathogenic:3

Mar 21, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 8 nucleotides in exon 7 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. This variant has been reported in individuals affected with or suspected of having Lynch syndrome or constitutional mismatch repair deficiency (PMID: 20487569, 25980754, 27064304, 27435373, 32642664). This variant has not been identified 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. -

Mar 20, 2014

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.746_753del8 pathogenic mutation located in coding exon 7 of the PMS2 gene, results from a deletion of 8 nucleotides at nucleotide positions 746 to 753, causing a translational frameshift with a predicted alternate stop codon. This mutation has been reported in a patient with colorectal cancer diagnosed at age 38 (Talseth-Palmer BA et al. Hered Cancer Clin Pract 2010; 8:5). In addition to the clinical data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Jun 25, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.746_753delACTCCGTG pathogenic mutation, located in coding exon 7 of the PMS2 gene, results from a deletion of 8 nucleotides at nucleotide positions 746 to 753, causing a translational frameshift with a predicted alternate stop codon (p.D249Vfs*2). This mutation has been reported in multiple individuals with a personal and/or family history of HNPCC/Lynch syndrome-associated cancers (Talseth-Palmer BA et al. Hered Cancer Clin Pract, 2010 May;8:5; Yurgelun MB et al. Gastroenterology, 2015 Sep;149:604-13.e20; van der Klift HM et al. Hum Mutat, 2016 11;37:1162-1179; Espenschied CR et al. J Clin Oncol, 2017 Aug;35:2568-2575). This mutation has also been detected in conjunction with a second PMS2 mutation in patients with features consistent with constitutional mismatch repair deficiency (CMMRD) syndrome (Guerrini-Rousseau L et al. Neurooncol Adv Dec;1:vdz033; Ambry internal data). 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 4 Pathogenic:2

Sep 19, 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. -

Apr 20, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Jan 23, 2025

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.Asp249Valfs*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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with colorectal cancer and suspected Lynch syndrome (PMID: 20487569, 25980754, 27064304, 27435373). 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: 142778). Studies have shown that this premature translational stop signal is associated with inconclusive levels of altered splicing (internal data). 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: rs587782710; hg19: chr7-6037006;