7-6003690-C-T

Position:

chr7-6003690-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_000535.7(PMS2):c.353G>A(p.Ser118Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,380,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S118S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PMS2
NM_000535.7 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6U:1

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:

PMS2 (HGNC:):

PMS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.865

PP5

Variant 7-6003690-C-T is Pathogenic according to our data. Variant chr7-6003690-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 525724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6003690-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7 linkuse as main transcript	c.353G>A	p.Ser118Asn	missense_variant, splice_region_variant	4/15	ENST00000265849.12	NP_000526.2	P54278-1Q7Z3Q2B4DGM0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12 linkuse as main transcript	c.353G>A	p.Ser118Asn	missense_variant, splice_region_variant	4/15	1	NM_000535.7	ENSP00000265849.7		P54278-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000426

AC:

AN:

234884

Hom.:

AF XY:

0.00000775

AC XY:

AN XY:

128996

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000918

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000145

AC:

AN:

1380492

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

691286

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000190

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

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	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 24, 2024	The PMS2 c.353G>A (p.Ser118Asn) variant has been reported in the published literature in individuals affected with colorectal cancer (PMID: 31992580 (2020), 38311346 (2024)) and breast cancer (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/PMS2)). Assessment of experimental evidence suggests this variant results in abnormal RNA splicing, resulting in premature termination of the protein (PMID: 31992580 (2020), 38311346 (2024)). The frequency of this variant in the general population, 0.0000043 (1/234884 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, this variant is classified as likely pathogenic. -

Hereditary nonpolyposis colorectal neoplasms

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 21, 2023

This sequence change affects codon 118 of the PMS2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PMS2 protein. This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has been observed in individuals with clinical features consistent with Lynch syndrome (PMID: 31992580; Invitae). ClinVar contains an entry for this variant (Variation ID: 525724). 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2021

The c.353G>A pathogenic mutation (also known as p.S118N), located in coding exon 4 of the PMS2 gene, results from a G to A substitution at nucleotide position 353. This change occurs in the last base pair of coding exon 4, which makes it likely to have some effect on normal mRNA splicing. In addition to the splicing impact, this alteration changes the serine residue to an asparagine residue at codon 118, an amino acid with highly similar properties. This variant has been identified in individuals whose Lynch syndrome-associated tumors demonstrated isolated loss of PMS2 staining on immunohistochemistry (Wang Q et al. J Med Genet, 2020 07;57:487-499; Ambry internal data). In one study, coding exon 4 skipping was reported for this variant upon PMS2 transcript analysis using RNA isolated from patient samples (Wang Q et al. J Med Genet, 2020 07;57:487-499). Both the nucleotide and amino acid positions are highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In addition, the missense alteration is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Lynch syndrome 4

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Sep 18, 2023

This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data]. -

Carcinoma of colon

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PMS2 p.Ser118Asn variant was not identified in the literature nor was it identified in the dbSNP, ClinVar, GeneInsight-COGR, COSMIC, MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, or the Insight Hereditary Tumors Database. The variant was identified in the LOVD Human Mismatch Repair Gene Database (1 entry, pathogenicity unknown). The variant was identified in control databases in 1 of 230230 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European Non-Finnish in 1 of 107116 chromosomes (freq: 0.000009), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Ser118Asn residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The p.Ser118Asn variant occurs in the last three bases of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. In addition, 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.76

D;.

Eigen

Uncertain

0.66

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.68

T;T

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.86

D;D

MetaSVM

Uncertain

0.51

MutationAssessor

Pathogenic

4.3

H;H

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-2.5

N;D

REVEL

Uncertain

0.64

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.026

D;D

Polyphen

0.58

P;B

Vest4

0.93

MutPred

0.59

Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);

MVP

0.92

MPC

0.22

ClinPred

0.99

GERP RS

5.7

Varity_R

0.96

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.84

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.84

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