NM_000535.7:c.2522G>A

Variant names:

• chr7-5973466-C-T
• rs876661203
• NM_000535.7:c.2522G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000535.7(PMS2):​c.2522G>A​(p.Trp841*) variant causes a stop gained change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 10)
• Consequence: PMS2 NM_000535.7 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.90
• 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 16 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 20 pathogenic variants in the truncated region.
• PP5: Variant 7-5973466-C-T is Pathogenic according to our data. Variant chr7-5973466-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 234759.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.2522G>A	p.Trp841*	stop_gained	Exon 15 of 15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.2522G>A	p.Trp841*	stop_gained	Exon 15 of 15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes Cov.: 10

GnomAD4 exome Cov.: 9

GnomAD4 genome Cov.: 10

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Jan 08, 2016

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted PMS2 c.2522G>A at the cDNA level and p.Trp841Ter (W841X) at the protein level. The substitution creates a nonsense variant, which changes a Tryptophan to a premature stop codon (TGG>TAG) , and is predicted to cause loss of normal protein function through protein truncation. Even though this frameshift occurs near the end of the gene in the last exon, and nonsense-mediated decay is not expected to occur, it is significant since the last 22 amino acids are no longer translated. Furthermore, the truncation would disrupt the nuclease domain (Fukui 2011). In addition, functional studies have shown that downstream residues are involved with zinc binding and variants at these downstream residues result in significant reduction of MMR activity (Kosinski 2008). Therefore, we consider this variant to be likely pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Jul 01, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change results in a premature translational stop signal in the PMS2 gene (p.Trp841*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 22 amino acids of the PMS2 protein. The frequency data for this variant in the population databases (ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has not been reported in the literature in individuals with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 234759). This variant disrupts the C-terminal portion of the MLH1 interaction domain (amino acids 675-850) 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). Other variant(s) that disrupt this region (p.Trp841Glyfs*10) have been determined to be pathogenic (PMID: 26116798, 30764633). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jun 21, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.W841* pathogenic mutation (also known as c.2522G>A), located in coding exon 15 of the PMS2 gene, results from a G to A substitution at nucleotide position 2522. This changes the amino acid from a tryptophan to a stop codon within coding exon 15. This alteration occurs at the 3' terminus of thePMS2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 22 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 alteration has been reported in an individual undergoing multigene panel testing for hereditary cancer (Roberts M et al. Genet. Med. 2018 10;20(10):1167-1174). Another alteration resulting in the same premature stop codon, c.2523G>A (p.W841*), has been identified in a male with breast cancer at age 69 years and also in a female with breast cancer at 41 years and a family history of breast and prostate cancer (Castera L et al. Eur. J. Hum. Genet. 2014 Nov;22(11):1305-13; Fostira F et al. Breast Cancer Res. Treat. 2018 May;169(1):105-113). A downstream truncating pathogenic mutation, p.W841Gfs*10, has also been identified in several individuals whose colorectal tumors demonstrated isolated loss of PMS2 expression on immunohistochemistry (IHC) (Ambry internal data). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Lynch syndrome 4 Pathogenic:1

Dec 27, 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 termination codon and is predicted to result in premature protein truncation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.9
Vest4		0.80
GERP RS		5.3
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs876661203; hg19: chr7-6013097;