rs1554292880

chr7-5973529-G-GT

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000535.7(PMS2):c.2458_2459insA(p.Thr820AsnfsTer4) 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:2
• Conservation: PhyloP100: 8.01

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 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 7-5973529-G-GT is Pathogenic according to our data. Variant chr7-5973529-G-GT is described in ClinVar as [Pathogenic]. Clinvar id is 434032.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.2458_2459insA	p.Thr820AsnfsTer4	frameshift_variant	15/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.2458_2459insA	p.Thr820AsnfsTer4	frameshift_variant	15/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes Cov.: 9

GnomAD4 exome Cov.: 6

GnomAD4 genome Cov.: 9

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lynch syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 15, 2023

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. ClinVar contains an entry for this variant (Variation ID: 434032). This premature translational stop signal has been observed in individual(s) with clinical features of constitutional mismatch repair deficiency syndrome (PMID: 24440087). 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 sequence change creates a premature translational stop signal (p.Thr820Asnfs*4) in the PMS2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 43 amino acid(s) of the PMS2 protein. This variant disrupts a region of the PMS2 protein in which other variant(s) (p.Asn823Lysfs*63) have been determined to be pathogenic (PMID: 31992580; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554292880; hg19: chr7-6013160;