chr7-5986766-C-T

Position:

chr7-5986766-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_000535.7(PMS2):c.1999G>A(p.Glu667Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000288 in 1,595,558 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 (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:13

Conservation

PhyloP100: 7.00

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:

PMS2 (HGNC:):

PMS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.37907705).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7 linkuse as main transcript	c.1999G>A	p.Glu667Lys	missense_variant	11/15	ENST00000265849.12	NP_000526.2	P54278-1Q7Z3Q2B4DGM0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12 linkuse as main transcript	c.1999G>A	p.Glu667Lys	missense_variant	11/15	1	NM_000535.7	ENSP00000265849.7		P54278-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000336

AC:

AN:

238424

Hom.:

AF XY:

0.0000465

AC XY:

AN XY:

128900

show subpopulations

Gnomad AFR exome

AF:

0.0000635

Gnomad AMR exome

AF:

0.00

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:

0.0000635

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000291

AC:

AN:

1443454

Hom.:

Cov.:

AF XY:

0.0000362

AC XY:

AN XY:

717346

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000243

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000352

Gnomad4 OTH exome

AF:

0.0000336

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 31, 2023	The p.E667K variant (also known as c.1999G>A), located in coding exon 11 of the PMS2 gene, results from a G to A substitution at nucleotide position 1999. The glutamic acid at codon 667 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in individuals diagnosed with peritoneal, colon, and pancreatic cancers (Kraus C et al. Int. J. Cancer. 2017 Jan;140:95-102; Xu HX et al. Am J Cancer Res. 2020 Nov;10:3920-3934; Yang XR et al. Hum Genet. 2016 Nov;135:1241-1249). This alteration has been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer. 2019 Jun;19:535). 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	curation	Sema4, Sema4	Oct 28, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 20, 2023	This missense variant replaces glutamic acid with lysine at codon 667 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with peritoneal cancer (PMID: 27616075), head and neck squamous cell carcinoma (PMID: 26689913), breast cancer (PMID: 35127508, 36011273; Duzkale et al. 2021), and colorectal cancer with a tumor showing MSH6 loss via immunohistochemistry but microsatellite stability (PMID: 33294277). This variant has been identified in 8/238424 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:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 16, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with peritoneal or other cancers undergoing multigene hereditary cancer testing (PMID: 27616075, 31159747, 35089076, 31391288); This variant is associated with the following publications: (PMID: 31159747, 33294277, 31391288, 35089076, 11292842, 27616075) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 15, 2023	The PMS2 c.1999G>A (p.Glu667Lys) variant has been reported in the published literature in individuals/families affected with colorectal cancer (PMID: 33294277 (2020)), breast and/or ovarian cancer (PMIDs: 31159747 (2019), 35127508 (2021), Duzkale et al. Turk J Clin Lab 3:346-356 (2021), 36011273 (2022)), pancreatic cancer (PMID: 27449771 (2016)), peritoneal cancer (PMID: 27616075 (2016)), head and neck squamous cell carcinoma (PMID: 26689913 (2015)), and unspecified cancers (PMID: 31391288 (2020), 35089076 (2022)). The frequency of this variant in the general population, 0.000063 (7/110292 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 11, 2023	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 21, 2023

Variant summary: PMS2 c.1999G>A (p.Glu667Lys) results in a conservative amino acid change in 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 3.4e-05 in 238424 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1999G>A has been reported in the literature as a VUS in settings of multigene panel testing among individuals affected with a variety of cancers (example, Kraus_2017, Yang_2016, Sahin_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27616075, 35089076, 27449771). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

PMS2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 24, 2024

The PMS2 c.1999G>A variant is predicted to result in the amino acid substitution p.Glu667Lys. This variant has been reported as a variant of uncertain significance in individuals affected with peritoneal cancer (Kraus et al. 2017. PubMed ID: 27616075), colorectal cancer (Xu et al. 2020. PMID: 33294277), breast and/or ovarian cancer (Tsaousis et al. 2019. PubMed ID: 31159747; Li et al. 2019. PubMed ID: 31391288). This variant is reported in 0.0063% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127769/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Lynch syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 23, 2024

This missense variant replaces glutamic acid with lysine at codon 667 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with peritoneal cancer (PMID: 27616075), colorectal cancer with immunohistochemistry showing MSH6 loss (PMID: 33294277), head and neck squamous cell carcinoma (PMID: 26689913), and breast cancer (PMID: 35127508, 36011273; Duzkale et al. 2021). This variant has been identified in 8/238424 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. -

Hereditary nonpolyposis colorectal neoplasms

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 667 of the PMS2 protein (p.Glu667Lys). This variant is present in population databases (rs587780045, gnomAD 0.007%). This missense change has been observed in individual(s) with with PMS2-related conditions (PMID: 27449771, 27616075, 33294277). ClinVar contains an entry for this variant (Variation ID: 127769). 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 with a positive predictive value of 80%. 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. -

Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jul 17, 2023

Criteria applied: PM2_SUP,PP3 -

Lynch syndrome 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Uncertain

0.095

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

T;.;.;.;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;.;D;.

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.38

T;T;T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Uncertain

2.8

M;.;.;.;.

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.4

N;N;.;.;.

REVEL

Benign

0.29

Sift

Benign

0.16

T;T;.;.;.

Sift4G

Uncertain

0.022

D;D;.;.;.

Polyphen

0.41

B;D;.;.;D

Vest4

0.80

MutPred

0.44

Loss of ubiquitination at K670 (P = 0.0255);.;.;.;.;

MVP

0.69

MPC

0.28

ClinPred

0.40

GERP RS

5.8

Varity_R

0.37

gMVP

0.48

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