7-5973457-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PP3_Moderate PP5_Very_Strong

The NM_000535.7(PMS2):c.2531C>A(p.Pro844His) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P844R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 10)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain in NM_000535.7
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.923
• PP5: Variant 7-5973457-G-T is Pathogenic according to our data. Variant chr7-5973457-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 142877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.2531C>A	p.Pro844His	missense_variant	15/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.2531C>A	p.Pro844His	missense_variant	15/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes Cov.: 10

GnomAD4 exome Cov.: 10

GnomAD4 genome Cov.: 10

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lynch syndrome 4 Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Feb 22, 2021	An individual with a clinical phenotype consistent with constitutional mismatch repair deficiency was homozygous for PMS2 p.P844H (Lavoine 2015), which is most consistent with a pathogenic classification. The PMS2 p.P844H variant is rare in population databases (gnomad.broadinstitute.org). -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 25, 2023	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 35451539]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 26318770, 33259954]. -

PMS2-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 30, 2023

The PMS2 c.2531C>A variant is predicted to result in the amino acid substitution p.Pro844His. This variant has been reported in the homozygous and presumed compound heterozygous state in three individuals with constitutional mismatch repair deficiency syndrome (Table 1, Lavoine et al. 2015. PubMed ID: 26318770; Table A1, Shuen et al. 2019. PubMed ID: 30608896; Table 1, Guerrini-Rousseau et al. 2019. PubMed ID: 32642664). It has been reported in an individual with a personal and/or family history of Lynch syndrome (Tables S1 and S11, Borras et al. 2017. PubMed ID: 28765196). In vitro experimental studies suggest this variant impairs mismatch repair activity (Table 1, Rayner et al. 2022. PubMed ID: 35451539). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142877/). This variant is interpreted as likely pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Apr 26, 2023

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in an individual homozygous for the variant and affected with constitutional mismatch repair deficiency syndrome (CMMRD) (PMID: 26318770 (2015)). Additionally, the variant has been reported in individuals with colorectal cancer (PMIDs: 30608896 (2019), 28765196 (2017)). Functional studies performed demonstrated reduced MMR activity (PMID: 30608896 (2019)). 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 pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 07, 2024

This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 844 of the PMS2 protein (p.Pro844His). 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 constitutional mismatch repair deficiency syndrome, Lynch syndrome (PMID: 26318770; Invitae). ClinVar contains an entry for this variant (Variation ID: 142877). 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 have shown that this missense change affects PMS2 function (PMID: 35451539). 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

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2023

The p.P844H variant (also known as c.2531C>A), located in coding exon 15 of the PMS2 gene, results from a C to A substitution at nucleotide position 2531. The proline at codon 844 is replaced by histidine, an amino acid with similar properties. This variant was reported in an individual that met Bethesda guidelines and was diagnosed at age 50 with microsatellite stable (MSS) colorectal cancer that demonstrated normal mismatch repair protein expression on immunohistochemistry (IHC) (Borras E et al. Cancer Prev Res (Phila), 2017 Oct;10:580-587). In a French cohort of 31 individuals with constitutional mismatch repair deficiency syndrome (CMMRD), this variant was reported as homozygous in an individual with a personal history of colorectal cancer/polyps at age 20, glioblastoma at age 32, and gastric carcinoma at age 32 (Lavoine N et al. J. Med. Genet., 2015 Nov;52:770-8). Furthermore, tumor testing performed on this proband's glioma demonstrated loss of PMS2 expression on immunohistochemistry (IHC) with high microsatellite instability (MSI-H) and loss of PMS2 expression on IHC was also seen in non-neoplastic cells (Lavoine N et al. J. Med. Genet., 2015 Nov;52:770-8; Guerrini-Rousseau L et al. Neuro-Oncology Advances, 2019 Nov;1(1):1-13; doi:10.1093/noajnl/vdz033). This variant has been reported in conjunction with PMS2 p.R421*, in an individual with a personal history of colorectal cancer and four tubular adenomas diagnosed at age 27, and functional studies performed demonstrated <10% MMR activity (Shuen AY et al. J Clin Oncol, 2019 02;37:461-470). This variant has also been identified in individuals whose Lynch syndrome associated tumors demonstrated loss of PMS2 expression on IHC, two of which also had a second somatic pathogenic PMS2 mutation identified (Ambry internal data, internal correspondence). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;.;.;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;.;D;.;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	4.7	H;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-7.7	D;D;.;.;.;D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;D;.;.;.;D
Sift4G	Pathogenic	0.0	D;D;.;.;.;D
Polyphen		1.0	D;D;.;.;D;D
Vest4		0.90
MutPred		0.72		Gain of MoRF binding (P = 0.0706);.;.;.;.;.;
MVP		0.96
MPC		3.5
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.84
gMVP		0.86

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

Other links and lift over

dbSNP: rs587782787; hg19: chr7-6013088;