rs730881916

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong

The NM_000535.7(PMS2):c.505C>T(p.Arg169Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000048 in 1,458,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 5.19

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 Uncertain_significance. Variant got 4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.943

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7 link	c.505C>T	p.Arg169Cys	missense_variant	Exon 5 of 15	ENST00000265849.12	NP_000526.2	P54278-1Q7Z3Q2B4DGM0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12 link	c.505C>T	p.Arg169Cys	missense_variant	Exon 5 of 15	1	NM_000535.7	ENSP00000265849.7		P54278-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249784

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135222

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

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:

0.00000480

AC:

AN:

1458864

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

725784

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000342

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Oct 29, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PMS2 c.505C>T (p.Arg169Cys) variant has been reported in the published literature in reportedly health individuals (PMID: 33471991 (2021), see also see also LOVD (http://databases.lovd.nl/shared)). The frequency of this variant in the general population, 0.000004 (1/249784 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 predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Mar 18, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 11574484) -

Hereditary cancer-predisposing syndrome

Uncertain:2

Mar 08, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with cysteine at codon 169 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has been identified in 1/249784 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Jun 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R169C variant (also known as c.505C>T), located in coding exon 5 of the PMS2 gene, results from a C to T substitution at nucleotide position 505. The arginine at codon 169 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

not specified

Uncertain:1

Apr 30, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PMS2 c.505C>T (p.Arg169Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249784 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.505C>T in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 182810). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary nonpolyposis colorectal neoplasms

Uncertain:1

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 169 of the PMS2 protein (p.Arg169Cys). This variant is present in population databases (rs730881916, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 182810). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt PMS2 function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.74

D;.;.;.;.;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

D;D;.;D;.;D

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.94

D;D;D;D;D;D

MetaSVM

Uncertain

0.77

MutationAssessor

Pathogenic

3.9

H;.;.;.;.;H

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-7.0

D;D;.;.;.;D

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;D;.;.;.;D

Sift4G

Pathogenic

0.0

D;D;.;.;.;D

Polyphen

1.0

D;D;.;.;D;D

Vest4

1.0

MutPred

0.79

Loss of MoRF binding (P = 0.0099);.;.;.;.;Loss of MoRF binding (P = 0.0099);

MVP

1.0

MPC

0.30

ClinPred

1.0

GERP RS

4.5

Varity_R

0.90

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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