rs375968016

chr7-5977596-G-Achr7-5977596-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1 PP3

The NM_000535.7(PMS2):c.2437C>T(p.Arg813Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000613 in 1,565,522 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R813G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000052 (1 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:10 B:1
• Conservation: PhyloP100: 5.11

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_000535.7
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.815

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.2437C>T	p.Arg813Trp	missense_variant	14/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.2437C>T	p.Arg813Trp	missense_variant	14/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes AF: 0.000148 AC: 22 AN: 148678 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000468

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000200

Gnomad SAS AF: 0.000215

Gnomad FIN AF: 0.0000993

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000107 AC: 22 AN: 206338 Hom.: 0 AF XY: 0.0000798 AC XY: 9 AN XY: 112764

Gnomad AFR exome AF: 0.000238

Gnomad AMR exome AF: 0.0000325

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.000216

Gnomad FIN exome AF: 0.000107

Gnomad NFE exome AF: 0.0000116

Gnomad OTH exome AF: 0.000568

GnomAD4 exome AF: 0.0000522 AC: 74 AN: 1416744 Hom.: 1 Cov.: 30 AF XY: 0.0000439 AC XY: 31 AN XY: 705676

Gnomad4 AFR exome AF: 0.000458

Gnomad4 AMR exome AF: 0.0000227

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000231

Gnomad4 SAS exome AF: 0.000225

Gnomad4 FIN exome AF: 0.0000381

Gnomad4 NFE exome AF: 0.0000196

Gnomad4 OTH exome AF: 0.000102

GnomAD4 genome AF: 0.000148 AC: 22 AN: 148778 Hom.: 0 Cov.: 30 AF XY: 0.000138 AC XY: 10 AN XY: 72394

Gnomad4 AFR AF: 0.000467

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000201

Gnomad4 SAS AF: 0.000215

Gnomad4 FIN AF: 0.0000993

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ESP6500AA AF: 0.000867 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000673 AC: 8

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:10 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2018	This variant is denoted PMS2 c.2437C>T at the cDNA level, p.Arg813Trp (R813W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. Although this variant was observed in large population cohorts, data in this region of PMS2 are not considered reliable due to high pseudogene homology (Lek 2016). This variant is located in a zinc binding motif in the endonuclease domain (Kosinski 2008, Fukui 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether PMS2 Arg813Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 22, 2023	In the published literature, the variant has been reported in individuals with a personal or family history of colorectal cancer (PMID: 26900293 (2016), 33413596 (2021)) and breast cancer (PMID: 35449176 (2022), 36200007 (2022)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in unaffected individuals (see LOVD (http://databases.lovd.nl/shared/genes/PMS2) and PMID: 33471991 (2021)). The frequency of this variant in the general population, 0.00035 (6/17216 chromosomes in East Asian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 06, 2023	Variant summary: PMS2 c.2437C>T (p.Arg813Trp) results in a non-conservative amino acid change located in the MutL, C-terminal, dimerisation domain (IPR014790) of 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 6.1e-05 in 1558782 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer (6.1e-05 vs 7.1e-05), allowing no conclusion about variant significance. Additionally, this allele frequency needs to be cautiously considered due to the possibility of the PMS2 pseudogene being captured. c.2437C>T has been reported in the literature in individuals affected with Colorectal Cancer (Chang_2016), therapy-related myeloid neoplasms (Singhal_2021), gastric cancer (Zhang_2021), and breast cancer (Hu_2022, Mittal_2022), however without strong evidence for causality (e.g., lack of co-segregation data). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26900293, 33413596, 35449176, 33850299, 34567566, 36200007). Six submitters have reported this variant to ClinVar after 2014 with conflicting assessments (uncertain significance, n = 5; likely pathogenic, n = 1). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 21, 2016	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 03, 2022	This missense variant replaces arginine with tryptophan at codon 813 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 been reported in individuals affected with colorectal cancer (PMID: 26900293, 34172528). This variant has been identified in 19/201724 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 10, 2024	The p.R813W variant (also known as c.2437C>T), located in coding exon 14 of the PMS2 gene, results from a C to T substitution at nucleotide position 2437. The arginine at codon 813 is replaced by tryptophan, an amino acid with dissimilar properties. One study detected this alteration in 1/103 Taiwanese colorectal cancer patients (Chang YC et al. World J. Gastroenterol., 2016 Feb;22:2314-25). This alteration has also been reported in a cohort of 235 new female breast caner patients from India (Mittal A et al. Ecancermedicalscience, 2022 Aug;16:1434). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Ovarian cancer Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Jan 01, 2022

- -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 09, 2024

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 813 of the PMS2 protein (p.Arg813Trp). 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 variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 127783). 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%. 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. -

Lynch syndrome 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 18, 2023

- -

Hereditary cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.51	D;.;.;.;.;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	1.0	D;D;.;D;.;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Pathogenic	3.8	H;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.0	D;D;.;.;.;D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;D;.;.;.;D
Sift4G	Pathogenic	0.0	D;D;.;.;.;D
Polyphen		1.0	D;D;.;.;D;D
Vest4		0.99
MVP		0.96
MPC		3.3
ClinPred		0.97	D
GERP RS		4.8
Varity_R		0.95
gMVP		0.91

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: rs375968016; hg19: chr7-6017227;