rs267608153

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_001322011.2(PMS2):c.-31G>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00000658 in 152,058 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

PMS2
NM_001322011.2 5_prime_UTR_premature_start_codon_gain

Scores

Splicing: ADA: 1.000

Clinical Significance

Likely pathogenic reviewed by expert panel P:12O:1

Conservation

PhyloP100: 3.87

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 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-5995534-C-A is Pathogenic according to our data. Variant chr7-5995534-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 91377.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-5995534-C-A is described in Lovd as [Pathogenic]. Variant chr7-5995534-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7 link	c.903G>T	p.Lys301Asn	missense_variant, splice_region_variant	8/15	ENST00000265849.12	NP_000526.2	P54278-1Q7Z3Q2B4DGM0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12 link	c.903G>T	p.Lys301Asn	missense_variant, splice_region_variant	8/15	1	NM_000535.7	ENSP00000265849.7		P54278-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152058

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251238

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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

Cov.:

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152058

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74256

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:12Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Lynch syndrome 4

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Feb 09, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 28, 2016	The PMS2 c.903G>T (p.Lys301Asn) missense variant has been reported in a heterozygous state in three unrelated individuals affected with a Lynch syndrome-associated tumor and showing isolated loss of PMS2 by immunohistochemistry (Senter et al. 2008). In addition, Suerink et al. (2016) reported three heterozygous carriers of the p.Lys301Asn variant from one family, wherein at least one individual was affected. The p.Lys301Asn variant was absent from 80 controls (Tomsic et al. 2013) and is reported at a frequency of 0.00009 in the Latino population of the Exome Aggregation Consortium, though this is based on only one allele in a region of good sequencing coverage. Functional studies used RT-PCR analyses of patient RNA as well as minigene assays to demonstrate that the p.Lys301Asn variant caused an out of frame skipping of exon 8 (van der Klift et al. 2015). Based on the evidence, the p.Lys301Asn variant is classified as likely pathogenic for Lynch syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 28, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 19, 2023	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 26247049, 27435373]. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 20, 2021	The PMS2 c.903G>T (p.Lys301Asn) variant is located at the last nucleotide of exon 8, and experimental studies have shown this variant causes skipping of exon 8, resulting in a frameshift and premature termination of PMS2 protein synthesis or absent mRNA expression (PMIDs: 26247049 (2015), 26110232 (2016)). In addition, the variant has been reported in individuals/families with Lynch syndrome-associated cancers (PMIDs: 27435373 (2016), 26110232 (2016), 25512458 (2015), 22577899 (2013), 18602922 (2008)). It has also been reported in an individual with CMMRD (PMID: 26318770 (2015)). The frequency of this variant in the general population, 0.000029 (1/34578 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 17, 2023	Located at the last nucleotide of the exon and demonstrated to result in aberrant splicing predicted to cause protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (Suerink et al., 2016; van der Klift et al., 2015; van der Klift et al., 2016); Observed in multiple individuals with personal or family histories of Lynch syndrome-associated cancers, many who had tumors that exhibited high microsatellite instability and/or abnormal PMS2 protein expression on immunohistochemistry (Senter et al., 2008; Goodenberger et al., 2016; Suerink et al., 2016; Martin-Morales et al., 2018; Wang et al., 2020); Observed in a patient with constitutional mismatch repair deficiency syndrome (CMMRD) in published literature, however a second pathogenic variant was not noted (Lavoine et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25856668, 32549215, 29922827, 28888541, 22577899, 18602922, 25512458, 26110232, 26269718, 25345868, 11574484, 26247049, 32571878, 30256826, 30787465, 31332305, 27435373, 31992580, 26318770) -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 26, 2024	The c.903G>T pathogenic mutation (also known as p.K301N), located in coding exon 8 of the PMS2 gene, results from a G to T substitution at nucleotide position 903. The lysine at codon 301 is replaced by asparagine, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 8, which makes it likely to have some effect on normal mRNA splicing. This alteration has been reported in multiple individuals with personal and/or family histories consistent with Lynch syndrome (ten Broeke SW et al. J. Clin. Oncol., 2015 Feb;33:319-25; Goodenberger ML et al. Genet. Med., 2016 Jan;18:13-9; Suerink M et al. Genet. Med., 2016 Apr;18:405-9; Martin-Morales L et al. PLoS One, 2018 Sep;13:e0203885) and several had isolated loss of PMS2 staining on immunohistochemistry in their Lynch-associated tumors (Senter L et al. Gastroenterology. 2008 August;135(2):419-28; Tomsic J et al. Clin. Genet. 2013 Mar; 83(3):238-43; van der Klift HM et al. Mol. Genet. Genomic Med 2015 Jul; 3(4):327-45). RNA studies have demonstrated that this alteration results in skipping of coding exon 8 (Ambry internal data; van der Klift HM et al. Mol. Genet. Genomic Med 2015 Jul; 3(4):327-45). One French individual diagnosed with constitutional mismatch repair deficiency syndrome (CMMRD) was found to carry the c.903G>T mutation in conjunction with another PMS2 pathogenic mutation (Lavoine N et al. J. Med. Genet., 2015 Nov;52:770-8). This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition, as a missense substitution this is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 10, 2022	This variant causes a G>T nucleotide substitution at the end of exon 8 in the PMS2 gene. Splice site prediction tools predicted RNA splicing impact at the intron 8 splice donor site. Functional RNA studies reported the variant transcript has complete skipping of exon 8 (r.804_903del and p.Tyr268*) as detected by RT-PCR on patient-derived RNA and corroborated in RNA assays (PMID: 26247049, 27435373, 31332305). This variant has been reported in multiple individuals with personal or family history of Lynch syndrome-associated cancer (PMID: 18602922, 25512458, 25856668, 26110232, 30256826), including tumor samples that showed microsatellite instability and loss of DNA mismatch repair protein (InSiGHT). This variant has also been reported in an individual diagnosed with constitutional mismatch repair deficiency (CMMR-D) syndrome (PMID: 26318770). This variant has been identified in 1/251238 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -

Lynch syndrome

Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Jun 21, 2019

G>non-G at last base of exon with 6 bases of the intron not GTRRGT (splicing aberration has not been quantified) -

Hereditary nonpolyposis colorectal neoplasms

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2024

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 301 of the PMS2 protein (p.Lys301Asn). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs267608153, gnomAD 0.003%). This missense change has been observed in individual(s) with constitutional mismatch repair deficiency (CMMR-D) syndrome and Lynch syndrome-related cancers (PMID: 18602922, 25856668, 26110232, 26318770, 27435373; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 91377). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 26247049; Invitae). For these reasons, this variant has been classified as Pathogenic. -

Hereditary breast ovarian cancer syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Apr 09, 2024

According to the ACMG SVI adaptation criteria we chose these criteria: PVS1 (very strong pathogenic): RNA studies: skipping of exon 8, NMD (r.804_903del; p.Tyr268*), PM2 (supporting pathogenic): gAD v4: 1/152058 alleles, PM3 (medium pathogenic): Lavoine 2015: 1 patient with recessive constitutional mismatch repair deficiency , PP4 (medium pathogenic): MSI high and/or abnormal PMS2 protein expression on immunohistochemistry -

Lynch syndrome 1

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Uncertain

0.039

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

T;.;.;.;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D;.;D;.

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.68

D;D;D;D;D

MetaSVM

Uncertain

0.46

MutationAssessor

Uncertain

2.5

M;.;.;.;.

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.7

D;D;.;.;.

REVEL

Uncertain

0.63

Sift

Benign

0.072

T;T;.;.;.

Sift4G

Benign

0.18

T;T;.;.;.

Polyphen

1.0

D;D;.;.;D

Vest4

0.70

MutPred

0.62

Loss of ubiquitination at K301 (P = 0.0297);.;.;.;.;

MVP

0.92

MPC

0.26

ClinPred

0.96

GERP RS

5.7

Varity_R

0.66

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.72

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.72

Position offset: 0

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