chr7-6003717-T-TC

Position:

chr7-6003717-T-TC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000535.7(PMS2):c.325_326insG(p.Glu109GlyfsTer30) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000263 in 151,980 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E109E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PMS2
NM_000535.7 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.30

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 7-6003717-T-TC is Pathogenic according to our data. Variant chr7-6003717-T-TC is described in ClinVar as [Pathogenic]. Clinvar id is 233300.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 linkuse as main transcript	c.325_326insG	p.Glu109GlyfsTer30	frameshift_variant	4/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12 linkuse as main transcript	c.325_326insG	p.Glu109GlyfsTer30	frameshift_variant	4/15	1	NM_000535.7	P3	P54278-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151980

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000169

AC:

AN:

236098

Hom.:

AF XY:

0.0000231

AC XY:

AN XY:

129590

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000986

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000917

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000485

AC:

AN:

1443120

Hom.:

Cov.:

AF XY:

0.00000557

AC XY:

AN XY:

718708

show subpopulations

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:

0.0000581

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.03e-7

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151980

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74224

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lynch syndrome 4

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 18, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	May 11, 2017	This c.325dup (p.Glu109Glyfs*30) variant has been reported in a cohort of 145 unrelated patients with colorectal cancer [PMID 20205264]. This variant has been observed in 3 heterozygous individuals from the ExAC population database (http://exac.broadinstitute.org/variant/7-6043348-T-TC). This 1bp duplication creates a frameshift and is predicted to create a premature stop codon 30 amino acid downstream, and to result in a loss of function of the PMS2 protein. This variant is thus classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 20, 2023	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2019	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; This variant is associated with the following publications: (PMID: 28637615, 20205264, 21261604, 25856668, 26110232, 26247049, 31616036, 31447099) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 05, 2022	- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 19, 2022	The c.325dupG pathogenic mutation, located in coding exon 4 of the PMS2 gene, results from a duplication of G at nucleotide position 325, causing a translational frameshift with a predicted alternate stop codon (p.E109Gfs*30). This variant has also been shown to be associated with abnormal splicing resulting in transcripts containing out-of-frame full or partial deletion of coding exon 4 (van der Klift HM et al. Mol. Genet. Genomic Med. 2015 Jul;3(4):327-45; Ambry internal data). This variant has been identified in several probands whose Lynch syndrome-associated tumors demonstrated high microsatellite instability (MSI-H) and/or isolated loss of PMS2 expression by immunohistochemistry (IHC) (Ambry internal data). This variant has been reported in an individual diagnosed with colon cancer at age 40 whose tumor showed loss of PMS2 staining on IHC (Vaughn CP et al. Hum. Mutat. 2010 May;31(5):588-93). This variant was also identified in trans with another pathogenic PMS2 mutation in two siblings with constitutional mismatch repair-deficiency (CMMR-D) syndrome. One sibling was diagnosed with a brain tumor at age 11 while the other was diagnosed with rectal adenomas at age 24, lentigines, and hyperpigmentation (Johannesma PC et al. Clin. Genet. 2011 Sep;80(3):243-55). In another study, this pathogenic mutation was reported in individuals with colon cancer and pituitary cancer (Goodenberger ML et al. Genet. Med. 2016 Jan;18(1):13-9). This variant was also reported in a proband with MSI-H colorectal cancer diagnosed at age 38 that demonstrated positive mismatch repair protein staining on IHC (Jansen AML et al. Eur J Hum Genet, 2020 03;28:333-338). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 18, 2023	This variant inserts 1 nucleotide in exon 4 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 several individuals affected with Lynch syndrome or colorectal cancer (PMID: 20205264, 25856668, 31616036). This variant has also been reported in siblings affected with constitutional mismatch repair deficiency (CMMRD) who carried a PMS2 variant in trans (PMID: 21261604). This variant has been identified in 4/236098 chromosomes 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. -

Lynch syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Aug 08, 2023

This variant is predicted to result in loss of protein function through nonsense-mediated or protein truncation. Loss of function is an established mechanism of disease. Functional studies suggest that this variant may have a splice effect predicted to result in loss-of-function, in addition to the frameshift effect (PMID: 26247049). This variant has been reported as heterozygous in multiple individuals with PMS2-related cancers (PMID: 20205264, 25856668, 31616036, 35739278). In addition, it has been reported in the compound heterozygous state in siblings with constitutional mismatch repair deficiency (PMID: 21261604). This variant is present in 4/236098 total alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). -

Hereditary nonpolyposis colorectal neoplasms

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 17, 2023

For these reasons, this variant has been classified as Pathogenic. Studies have shown that this premature translational stop signal alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 26247049). ClinVar contains an entry for this variant (Variation ID: 233300). This premature translational stop signal has been observed in individual(s) with colorectal cancer and/or constitutional mismatch repair deficiency (PMID: 20205264, 21261604). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs762485848, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Glu109Glyfs*30) 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over