7-5982930-T-G

Position:

chr7-5982930-T-G

Variant summary

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

The ENST00000265849.12(PMS2):c.2068A>C(p.Lys690Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000027 in 1,592,150 control chromosomes in the GnomAD database, including 1 homozygotes. 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. K690R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000023 ( 1 hom. )

Consequence

PMS2
ENST00000265849.12 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:1

Conservation

PhyloP100: 6.10

Variant links:

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]

PMS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7 linkuse as main transcript	c.2068A>C	p.Lys690Gln	missense_variant	12/15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12 linkuse as main transcript	c.2068A>C	p.Lys690Gln	missense_variant	12/15	1	NM_000535.7	ENSP00000265849	P3	P54278-1

Frequencies

GnomAD3 genomes

AF:

0.0000659

AC:

AN:

151712

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.0000461

AC:

AN:

216714

Hom.:

AF XY:

0.0000592

AC XY:

AN XY:

118240

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000320

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000750

Gnomad OTH exome

AF:

0.000367

GnomAD4 exome

AF:

0.0000229

AC:

AN:

1440438

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

715576

show subpopulations

Gnomad4 AFR exome

AF:

0.0000307

Gnomad4 AMR exome

AF:

0.0000233

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000182

Gnomad4 OTH exome

AF:

0.0000674

GnomAD4 genome

AF:

0.0000659

AC:

AN:

151712

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74088

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000132

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.000480

Alfa

AF:

0.0000868

Hom.:

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 14, 2023	Variant summary: PMS2 c.2068A>C (p.Lys690Gln) results in a conservative amino acid change located in the C-terminal dimerisation domain (IPR014790) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 247978 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer (4.4e-05 vs 7.1e-05), allowing no conclusion about variant significance. In addition, the variant is located in a region that is highly homologous to PMS2 pseudogenes and the technology utilized for these datasets does not rule out pseudogene interference, therefore these data might not be reliable. The variant, c.2068A>C, has been reported in the literature in individuals affected with breast cancer and in another individual with endometrial carcinoma (Tung_2015, Ring_2016, Sahin_2022, Abdel-Razeq_2022), however it was also found in two individuals in a non-cancer related cohort (Kraemer_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. At least one co-occurrence with another pathogenic variants has been reported (BRCA2 c.8904delC, p.V2969fs*7, our internal data), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance. 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	Jan 20, 2022	This sequence has been previously described in individuals with breast cancer (PMID: 25186627) and endometrial cancer (PMID: 27443514). This sequence change has been described in the gnomAD database with a frequency of 0.0044% (dbSNP rs587781909); however, the frequency data for this variant in the population databases is considered unreliable due to its location in a region that is highly homologous to PMS2 pseudogenes. The p.Lys690Gln change affects a moderately conserved amino acid residue located in a domain of the PMS2 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, Align GVGD, REVEL) provide contradictory results for the p.Lys690Gln substitution. Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Lys690Gln change remains unknown at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Sep 29, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 30, 2023	The p.K690Q variant (also known as c.2068A>C), located in coding exon 12 of the PMS2 gene, results from an A to C substitution at nucleotide position 2068. The lysine at codon 690 is replaced by glutamine, an amino acid with similar properties. This alteration has been reported in a cohort of 381 endometrial carcinoma patients who had undergone tumor testing to screen for Lynch syndrome (Ring KL et al. Mod. Pathol., 2016 Nov;29:1381-1389). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be inconclusive 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	Jan 10, 2023	This missense variant replaces lysine with glutamine at codon 690 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 11/247978 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. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 25, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2024	Observed in individuals with endometrial, colorectal, or breast cancer (PMID: 25186627, 27443514, 33120919, 35402282, 37534630); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27443514, 25186627, 31422574, 35402282, 2744351, 33120919, 35089076, 37534630) -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

May 21, 2020

- -

Lynch syndrome 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 08, 2023

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Uncertain

0.032

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

T;.;.;.;.;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

D;D;.;D;.;D

M_CAP

Benign

0.066

MetaRNN

Uncertain

0.59

D;D;D;D;D;D

MetaSVM

Uncertain

-0.11

MutationAssessor

Uncertain

2.1

M;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;N

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-2.9

D;D;.;.;.;D

REVEL

Uncertain

0.51

Sift

Benign

0.14

T;T;.;.;.;T

Sift4G

Uncertain

0.0080

D;D;.;.;.;T

Polyphen

0.39

B;D;.;.;D;D

Vest4

0.65

MutPred

0.50

Loss of ubiquitination at K690 (P = 0.0224);.;.;.;.;.;

MVP

0.83

MPC

3.0

ClinPred

0.83

GERP RS

4.7

Varity_R

0.67

gMVP

0.62

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over