7-5977595-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000535.7(PMS2):c.2438G>A(p.Arg813Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R813W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.000011 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 7.90

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 Likely_pathogenic. Variant got 6 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
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.892

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.2438G>A	p.Arg813Gln	missense_variant	14/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.2438G>A	p.Arg813Gln	missense_variant	14/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.0000195 AC: 4 AN: 205050 Hom.: 0 AF XY: 0.00000892 AC XY: 1 AN XY: 112054

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000192

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000117

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000113 AC: 16 AN: 1415206 Hom.: 0 Cov.: 30 AF XY: 0.00000851 AC XY: 6 AN XY: 704896

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000227

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000769

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000103

Gnomad4 OTH exome AF: 0.0000170

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 23, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 06, 2017	This variant is denoted PMS2 c.2438G>A at the cDNA level, p.Arg813Gln (R813Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant has not, to our knowledge, been published in the literature as either a pathogenic germline variant or a benign polymorphism. However, it has been reported as a somatic variant in a colorectal cancer specimen (Kim 2015). PMS2 Arg813Gln was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. PMS2 Arg813Gln occurs at a position that is conserved across species and is within the endonuclease domain (Fukui 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether PMS2 Arg813Gln is pathogenic or benign. We consider it to be a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2019	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 22, 2023	This missense variant replaces arginine with glutamine 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 breast cancer (PMID: 29752822, 32547938), or endometrial case with microsatellite stability and normal immunohistochemistry results (PMID: 31307542). This variant has been identified in 4/205050 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	Nov 17, 2023	The p.R813Q variant (also known as c.2438G>A), located in coding exon 14 of the PMS2 gene, results from a G to A substitution at nucleotide position 2438. The arginine at codon 813 is replaced by glutamine, an amino acid with highly similar properties. This alteration was identified in a Chinese individual diagnosed with endometrial cancer and a Chinese individual diagnosed with breast cancer (Chao X et al. Cancer Commun (Lond), 2019 07;39:42; Li JY et al. Int. J. Cancer, 2019 01;144:281-289). Additionally, this alteration was identified in 1/711 individuals with breast cancer and 0/492 controls (Nikitin AG et al. Front Oncol, 2020 May;10:666). 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)). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 09, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 813 of the PMS2 protein (p.Arg813Gln). 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 individual(s) with breast cancer (PMID: 29752822, 35449176). ClinVar contains an entry for this variant (Variation ID: 418793). 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. 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. -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PMS2 p.Arg813Gln variant was identified in 1 of 222 proband chromosomes (frequency: 0.005) from individuals with endometrial cancer (Chao 2019). The variant was identified in dbSNP (rs587782665) as “with uncertain significance allele” and ClinVar (classified as uncertain significance by Invitae, Ambry Genetics and GeneDx). The variant was identified in control databases in 4 of 205,050 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 3 of 15,664 chromosomes (freq: 0.0002) and European in 1 of 85,616 chromosomes (freq: 0.00001), while it was not observed in the African, Latino, Ashkenazi Jewish, Finnish, Other or South Asian populations. The p.Arg813 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a 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	0.69
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	T;.;.;.;.;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;.;D;.;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Pathogenic	3.8	H;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.5	D;D;.;.;.;D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D;.;.;.;D
Sift4G	Pathogenic	0.0	D;D;.;.;.;D
Polyphen		1.0	D;D;.;.;D;D
Vest4		0.97
MutPred		0.65		Loss of MoRF binding (P = 0.05);.;.;.;.;.;
MVP		0.95
MPC		3.4
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.92
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

Other links and lift over

dbSNP: rs587782665; hg19: chr7-6017226;