7-5995614-G-A

Position:

chr7-5995614-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000535.7(PMS2):c.823C>T(p.Gln275Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,612,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q275Q) has been classified as Likely pathogenic. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

PMS2
NM_000535.7 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:17

Conservation

PhyloP100: 1.62

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 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 7-5995614-G-A is Pathogenic according to our data. Variant chr7-5995614-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 127796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5995614-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7 linkuse as main transcript	c.823C>T	p.Gln275Ter	stop_gained	8/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12 linkuse as main transcript	c.823C>T	p.Gln275Ter	stop_gained	8/15	1	NM_000535.7	P3	P54278-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251410

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1460578

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726680

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 18, 2022	This nonsense variant causes the premature termination of PMS2 protein synthesis. The frequency of this variant in the general population, 0.000008 (2/251410 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with Lynch syndrome (PMIDs: 31992580 (2020), 25512458 (2015), 23012243 (2013)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 05, 2022	Nonsense 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium; This variant is associated with the following publications: (PMID: 24689082, 26681312, 28514183, 26110232, 23012243, 25512458, 31992580, 31447099, 30787465, 33087929, 22848017) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 03, 2022	- -

Lynch syndrome 4

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 22, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Nov 26, 2017	This c.823C>T (p.Gln275) variant in the PMS2 gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple patients with cancer (PMID: 22848017, 25512458, 24689082, 26681312). The c.823C>T (p.Gln275) variant in the PMS2 gene is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 19, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Apr 26, 2021	ACMG codes:PVS1; PS4M; PM2; PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 02, 2022	- -

Lynch syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 14, 2019	The p.Gln275X variant in PMS2 has been reported in at least 4 heterozygous individuals with PMS2-associated cancers and in 1 compound heterozygous individual with constitutive mismatch repair deficiency (Espenschied 2017, Susswein 2016, Suerink 2016, Hansen 2014, Vaughn 2013, Yeung 2013). This variant has been identified in 2/34590 of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (pathogenic by several clinical labs (ClinVar ID 127796). This nonsense variant leads to a premature termination codon at position 275, which is predicted to lead to a truncated or absent protein. Loss of function of the PMS2 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting, PM3. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	The c.823C>T (p.Gln275) variant in the PMS2 gene is located on the exon 8 and introduces a premature translation termination codon (p.Gln275), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with Lynch syndrome-associated cancer or constitutional mismatch repair-deficiency syndrome (PMID: 28514183, 24689082, 27435373, 26110232, 23012243, 22848017). Loss-of-function variants in PMS2 are known to be pathogenic and variants located downstream to this position in this exon have been reported as pathogenic (PMID: 28514183, 25512458, 35223509, p.Gln288fs, ClinVar ID: 91376). The variant is reported in ClinVar (ID: 127796). The variant is rare in the general population according to gnomAD (2/251410). Therefore, the c.823C>T (p.Gln275*) variant of PMS2 has been classified as pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 11, 2022	The p.Q275* pathogenic mutation (also known as c.823C>T), located in coding exon 8 of the PMS2 gene, results from a C to T substitution at nucleotide position 823. This changes the amino acid from a glutamine to a stop codon within coding exon 8. This mutation has been reported in two Hereditary Non-Polyposis Colorectal Cancer (HNPCC)/Lynch syndrome families in the Netherlands (ten Broeke SW et al. J. Clin. Oncol. 2015 Feb;33(4):319-25); in a child diagnosed with constitutional mismatch repair deficiency (CMMR-D) who also had a second PMS2 mutation (Yeung JT et al. Pediatr Blood Cancer. 2013 Jan;60(1):137-9); and in a patient with endometrial cancer (Susswein LR et al. Genet. Med. 2016 Aug;18(8):823-32). 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 05, 2023	This variant changes 1 nucleotide in exon 8 of the PMS2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with constitutional mismatch mismatch repair deficiency who also carried another pathogenic PMS2 variant in trans (PMID: 22848017), as well as in multiple individuals affected with Lynch syndrome (PMID: 25512458, 27435373, 31992580). This variant has been identified in 2/251410 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 4;C5399763:Mismatch repair cancer syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Hereditary nonpolyposis colon cancer

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 28, 2020

Variant summary: PMS2 c.823C>T (p.Gln275X) 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 pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 251410 control chromosomes (gnomAD). c.823C>T has been reported in the literature in multiple individuals affected with colorectal cancer and Lynch syndrome (Yeung_2013, Hansen_2014, ten Broeke_2015, van der Klift_2016, Wang_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Hereditary nonpolyposis colorectal neoplasms

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

This sequence change creates a premature translational stop signal (p.Gln275*) 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 present in population databases (rs587780062, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome, and constitutional mismatch repair deficiency (PMID: 23012243, 24689082, 26110232). ClinVar contains an entry for this variant (Variation ID: 127796). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Benign

-0.070

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.15

MutationTaster

Benign

1.0

A;A;A;A;N

Vest4

0.92

GERP RS

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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