rs587781317

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000535.7(PMS2):c.2095G>C(p.Asp699His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,822 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 Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 7.90

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

PP5

Variant 7-5982903-C-G is Pathogenic according to our data. Variant chr7-5982903-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 140847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7 linkuse as main transcript	c.2095G>C	p.Asp699His	missense_variant	12/15	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.2095G>C	p.Asp699His	missense_variant	12/15	1	NM_000535.7	ENSP00000265849.7		P54278-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1447822

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719870

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:

9.06e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 2023	Identified in the heterozygous state in patients with Lynch-related cancers or with a tumor demonstrating isolated loss of PMS2 expression via immunohistochemistry (Vaughn et al., 2010; Roberts et al., 2014; Wang et al., 2020); Published functional studies demonstrate a damaging effect: impaired MMR activity (Arora et al., 2017; D'Arcy et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25856668, 31391288, 24113346, 23012243, 31992580, 29345684, 20205264, 23729388, 28494185, 35189042, 18619468) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 17, 2024	The PMS2 c.2095G>C (p.Asp699His) variant has been reported in the published literature in individuals with Lynch syndrome (PMIDs: 34357101 (2021), 31992580 (2020)), unspecified Lynch syndrome-associated tumors (PMIDs: 31391288 (2020), 23012243 (2013), 20205264 (2010)), colorectal cancer (PMID: 29345684 (2018), breast cancer (PMID: 24113346 (2014)), and osteosarcoma (PMID: 32191290 (2020)). This variant in the homozygous state has also been reported in an individual with constitutional mismatch repair deficiency (CMMRD) syndrome (PMID: 23729388 (2013)). Experimental studies indicate this variant is either moderately functional (PMID: 28494185 (2017)), or has a deleteriously effect on DNA mismatch repair activity (PMID: 35189042 (2022)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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, this variant is classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 13, 2021	PP3, PP4, PM2, PM3 -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 28, 2024	The c.2095G>C (p.D699H) alteration is located in coding exon 12 of the PMS2 gene. This alteration results from a G to C substitution at nucleotide position 2095, causing the aspartic acid (D) at amino acid position 699 to be replaced by a histidine (H). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was identified in several individuals whose family history met Amsterdam criteria (Ambry internal data). This variant has also been identified in patients with Lynch syndrome-associated tumors and microsatellite instability and/or isolated loss of PMS2 expression by immunohistochemistry (IHC) (Bouras, 2024; Ambry internal data). This alteration was also reported homozygous in a child with features suggestive of constitutional mismatch repair deficiency (CMMR-D); however, no tumor testing was performed (Walter, 2013). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, this variant sits at the interface between PMS2/MutLa and is anticipated to result in a significant decrease in structural stability (Gueneau, 2013). In vitro studies have shown that the p.D699H variant exhibits expression levels similar to wildtype; however, protein function was reduced (Arora, 2017). In another functional study, this variant showed reduced mismatch repair activity compared to wild type PMS2 (D'Arcy, 2022). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Mar 16, 2022	- -

Lynch syndrome 4

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 14, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 06, 2023	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 35189042, 16873062, 18619468]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been observed homozygous in one or more individuals with Constitutional Mismatch Repair Deficiency Syndrome (CMMRD) [PMID: 23729388]. -

PMS2-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 29, 2024

The PMS2 c.2095G>C variant is predicted to result in the amino acid substitution p.Asp699His. This variant has been reported in individuals with Lynch syndrome related cancers (Vaughn et al. 2010. PubMed ID: 20205264; Vaughn et al. 2013. PubMed ID: 23012243), and observed in the homozygous state in a patient with constitutional mismatch repair deficiency (Walter et al. 2013. PubMed ID: 23729388). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic or pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/140847/). This variant is interpreted as likely pathogenic. -

Hereditary nonpolyposis colon cancer

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Oct 16, 2023

Variant summary: PMS2 c.2095G>C (p.Asp699His) results in a non-conservative amino acid change located in the MutL, C-terminal, dimerisation of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 221718 control chromosomes. c.2095G>C has been reported in the literature, including one patient whose tumors showed isolated loss of PMS2 by immunohistochemistry (Vaughn_2010), and in a child with constitutional mismatch repair deficiency who carried the variant in the homozygous state (Walter_2013). It has also been reported as a class 3 variant in an individual with MSI-high colorectal cancer and equivocal IHC analysis who underwent a comprehensive PMS2 analysis (example, Wang_2020). In addition, the variant has been reported in other patients being tested by various NGS cancer panels, without long-range PCR to confirm lack of pseudogene interference (Espenschied_2017, Goodenberger_2015, Mauer_2013, Roberts_2018, Li_2019). An in vitro functional study showed the variant to have proficient RNA expression and protein expression, with reduced viability leading authors to described the variant as moderately functional (Arora_2017). Another functional study demonstrated reduced mismatch repair capacity (MMR) as compared to wild-type (D'Arcy_2022). The following publications have been ascertained in the context of this evaluation (PMID: 28494185, 35189042, 28514183, 25856668, 31391288, 24113346, 29345684, 20205264, 23729388, 31992580). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Hereditary nonpolyposis colorectal neoplasms

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 699 of the PMS2 protein (p.Asp699His). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This missense change has been observed in individuals with clinical features of Lynch syndrome or autosomal recessive constitutional mismatch repair deficiency (PMID: 20205264, 23012243, 23729388, 28514183; Invitae). ClinVar contains an entry for this variant (Variation ID: 140847). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMS2 protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PMS2 function (PMID: 28494185). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

T;.;.;.;.;.

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D;.;D;.;D

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D

MetaSVM

Pathogenic

0.93

MutationAssessor

Pathogenic

3.7

H;.;.;.;.;.

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-5.9

D;D;.;.;.;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D;.;.;.;D

Sift4G

Uncertain

0.0020

D;D;.;.;.;D

Polyphen

1.0

D;D;.;.;D;D

Vest4

0.98

MutPred

0.90

Loss of catalytic residue at D699 (P = 0.029);.;.;.;.;.;

MVP

0.98

MPC

3.5

ClinPred

1.0

GERP RS

4.7

Varity_R

0.94

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

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