7-5997402-C-G

Position:

• chr7-5997402-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1 BP4

The ENST00000265849.12(PMS2):​c.727G>C​(p.Val243Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000043 in 1,396,564 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V243F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: PMS2 ENST00000265849.12 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.98

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 1 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 16 uncertain in ENST00000265849.12
• BP4: Computational evidence support a benign effect (MetaRNN=0.31492332).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7	c.727G>C	p.Val243Leu	missense_variant	7/15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.727G>C	p.Val243Leu	missense_variant	7/15	1	NM_000535.7	ENSP00000265849	P3

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 0.00000430 AC: 6 AN: 1396564 Hom.: 0 Cov.: 29 AF XY: 0.00000287 AC XY: 2 AN XY: 697312

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000153

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 28

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 28, 2019	This missense variant replaces valine with leucine at codon 243 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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 31, 2018	The p.V243L variant (also known as c.727G>C), located in coding exon 7 of the PMS2 gene, results from a G to C substitution at nucleotide position 727. The valine at codon 243 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2021

This sequence change replaces valine with leucine at codon 243 of the PMS2 protein (p.Val243Leu). The valine residue is moderately conserved and there is a small physicochemical difference between valine and leucine. 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. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with PMS2-related conditions. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.;.;.;.;.
Eigen	Benign	0.087
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.91	D;D;.;D;.;D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.31	T;T;T;T;T;T
MetaSVM	Uncertain	-0.030	T
MutationAssessor	Uncertain	2.2	M;.;.;.;.;M
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.2	N;N;.;.;.;N
REVEL	Uncertain	0.34
Sift	Benign	0.44	T;T;.;.;.;T
Sift4G	Benign	0.30	T;T;.;.;.;T
Polyphen		0.010	B;P;.;.;P;P
Vest4		0.42
MutPred		0.49		Gain of catalytic residue at V243 (P = 0.0654);.;.;.;.;Gain of catalytic residue at V243 (P = 0.0654);
MVP		0.82
MPC		0.039
ClinPred		0.89	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.23
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs867655834; hg19: chr7-6037033;