rs63750770

Positions:

• chr7-5987032-C-A
• chr7-5987032-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000535.7(PMS2):​c.1733G>T​(p.Arg578Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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. R578H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 2.04

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 6 benign, 17 uncertain in NM_000535.7
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34398723).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.1733G>T	p.Arg578Leu	missense_variant	11/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.1733G>T	p.Arg578Leu	missense_variant	11/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 19, 2023	The p.R578L variant (also known as c.1733G>T), located in coding exon 11 of the PMS2 gene, results from a G to T substitution at nucleotide position 1733. The arginine at codon 578 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 06, 2019	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 11, 2016

This variant is denoted PMS2 c.1733G>T at the cDNA level, p.Arg578Leu (R578L) at the protein level, and results in the change of an Arginine to a Leucine (CGT>CTT). This variant has not, to our knowledge, been reported as a germline pathogenic or benign variant; however, it has been reported by Balogh et al. (2006) as a somatic variant observed in breast tumors. PMS2 Arg578Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Arg578Leu occurs at a position that is not conserved and is not located in a known functional domain (Guarne 2001, Fukui 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether PMS2 Arg578Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 30, 2021

This sequence change replaces arginine with leucine at codon 578 of the PMS2 protein (p.Arg578Leu). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). 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: 421090). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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	Benign	0.14
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T;.;.;.;.
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.69	T;T;.;T;.
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.34	T;T;T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.7	M;.;.;.;.
MutationTaster	Benign	1.0	D;D;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-3.3	D;D;.;.;.
REVEL	Uncertain	0.34
Sift	Uncertain	0.026	D;D;.;.;.
Sift4G	Benign	0.15	T;T;.;.;.
Polyphen		0.98	D;D;.;.;D
Vest4		0.42
MutPred		0.45		Loss of solvent accessibility (P = 0.0299);.;.;.;.;
MVP		0.52
MPC		0.057
ClinPred		0.78	D
GERP RS		5.0
Varity_R		0.41
gMVP		0.34

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: rs63750770; hg19: chr7-6026663;