rs867655834

Positions:

• chr7-5997402-C-A
• chr7-5997402-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1

The NM_000535.7(PMS2):​c.727G>T​(p.Val243Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. V243L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000091 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• 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 2 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 16 uncertain in NM_000535.7

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.727G>T	p.Val243Phe	missense_variant	7/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.727G>T	p.Val243Phe	missense_variant	7/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 26 AN: 121238 Hom.: 0 Cov.: 28 FAILED QC

Gnomad AFR AF: 0.000284

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000903

Gnomad ASJ AF: 0.000323

Gnomad EAS AF: 0.000227

Gnomad SAS AF: 0.000537

Gnomad FIN AF: 0.000154

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000172

Gnomad OTH AF: 0.000611

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000910 AC: 127 AN: 1395922 Hom.: 0 Cov.: 29 AF XY: 0.0000961 AC XY: 67 AN XY: 696938

Gnomad4 AFR exome AF: 0.0000953

Gnomad4 AMR exome AF: 0.000193

Gnomad4 ASJ exome AF: 0.000118

Gnomad4 EAS exome AF: 0.000153

Gnomad4 SAS exome AF: 0.000219

Gnomad4 FIN exome AF: 0.0000379

Gnomad4 NFE exome AF: 0.0000774

Gnomad4 OTH exome AF: 0.0000861

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000214 AC: 26 AN: 121302 Hom.: 0 Cov.: 28 AF XY: 0.000224 AC XY: 13 AN XY: 57950

Gnomad4 AFR AF: 0.000283

Gnomad4 AMR AF: 0.0000902

Gnomad4 ASJ AF: 0.000323

Gnomad4 EAS AF: 0.000227

Gnomad4 SAS AF: 0.000540

Gnomad4 FIN AF: 0.000154

Gnomad4 NFE AF: 0.000172

Gnomad4 OTH AF: 0.000606

Alfa AF: 0.0000882 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

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	Jun 12, 2017	The p.V243F variant (also known as c.727G>T), located in coding exon 7 of the PMS2 gene, results from a G to T substitution at nucleotide position 727. The valine at codon 243 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is highly 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 09, 2018	- -

Lynch syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

University of Washington Department of Laboratory Medicine, University of Washington

May 01, 2018

PMS2 NM_000535.5:c.727G>T has a 16.7% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.20 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the PMS2 locus. See Shirts et al 2018, PMID 29887214. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 15, 2016

This variant is denoted PMS2 c.727G>T at the cDNA level, p.Val243Phe (V243F) at the protein level, and results in the change of a Valine to a Phenylalanine (GTT>TTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Val243Phe 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 Valine and Phenylalanine differ in some properties, this is considered a semi-conservative amino acid substitution. PMS2 Val243Phe occurs at a position that is conserved in mammals and is located in the ATPase domain (Guarne 2001). 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 Val243Phe 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

Sep 21, 2021

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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 419274). This missense change has been observed in individual(s) with breast cancer (PMID: 29752822). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with phenylalanine at codon 243 of the PMS2 protein (p.Val243Phe). The valine residue is moderately conserved and there is a small physicochemical difference between valine and phenylalanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;.;.;.;.;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.94	D;D;.;D;.;D
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.42	T;T;T;T;T;T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Uncertain	2.9	M;.;.;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.7	D;N;.;.;.;N
REVEL	Uncertain	0.58
Sift	Benign	0.063	T;T;.;.;.;T
Sift4G	Uncertain	0.050	T;T;.;.;.;T
Polyphen		0.81	P;D;.;.;D;D
Vest4		0.66
MutPred		0.51		Loss of helix (P = 0.1299);.;.;.;.;Loss of helix (P = 0.1299);
MVP		0.92
MPC		0.18
ClinPred		0.40	T
GERP RS		5.4
Varity_R		0.48
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: -6

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;