7-6002524-T-C

Position:

chr7-6002524-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The ENST00000265849.12(PMS2):c.466A>G(p.Thr156Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,611,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. T156I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PMS2
ENST00000265849.12 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 5.87

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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.749

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7 linkuse as main transcript	c.466A>G	p.Thr156Ala	missense_variant	5/15	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.466A>G	p.Thr156Ala	missense_variant	5/15	1	NM_000535.7	ENSP00000265849	P3	P54278-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000798

AC:

AN:

250722

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135602

show subpopulations

Gnomad AFR exome

AF:

0.0000623

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:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1459396

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726046

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000283

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lynch syndrome 4

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 04, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 12, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 03, 2023	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 07, 2023	In the published literature, this variant has been reported in affected individuals with breast cancer (PMIDs: 26320870 (2015) and 35449176 (2022)), as well as colorectal cancer (PMID: 26320870 (2015)). Functional studies demonstrated reduced interaction with Akt kinase and increased stability of PMS2 protein (PMIDs: 23499907 (2013) and 26423401 (2016)). The frequency of this variant in the general population, 0.000008 (2/250722 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 predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with colon and/or breast cancer (PMID: 26320870, 35449176); This variant is associated with the following publications: (PMID: 26423401, 23499907, 34626046, 35449176, 28767177, 11574484, 26320870) -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 02, 2023	This missense variant replaces threonine with alanine at codon 156 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). A functional study has shown that the variant may result in the loss of phosphorylation induced by Akt kinase and increased stability of the PMS2 protein (PMID: 26423401). However, the clinical relevance of this observation is not known. This variant has been reported in an individual affected with colon and breast cancer (PMID: 26320870). This variant has been identified in 2/250722 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 05, 2023	The p.T156A variant (also known as c.466A>G), located in coding exon 5 of the PMS2 gene, results from an A to G substitution at nucleotide position 466. The threonine at codon 156 is replaced by alanine, an amino acid with similar properties. This alteration was identified in an individual diagnosed with colon and breast cancer at age 52 who also had a family history of cancer (Li J et al. J Mol Diagn, 2015 Sep;17:545-53). In one functional study, this alteration demonstrated reduced interaction with Akt kinase and increased PMS2 protein stability (Jia J et al. Cell. Signal., 2013 Jun;25:1498-504). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Lynch syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jul 22, 2023

This missense variant replaces threonine with alanine at codon 156 of the PMS2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on protein structure and function. Computational splicing tools suggest that this variant may not impact RNA splicing. Functional study has shown that the variant may result in the loss of phosphorylation induced by Akt kinase and increased stability of PMS2 protein (PMID: 26423401). However, clinical relevance of this observation is not known. This variant has been reported in an individual affected with colon and breast cancer (PMID: 26320870). This variant has been identified in 2/250722 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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

Jan 21, 2024

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 156 of the PMS2 protein (p.Thr156Ala). This variant is present in population databases (rs786204206, gnomAD 0.007%). This missense change has been observed in individual(s) with colon and breast cancer (PMID: 26320870, 35449176). ClinVar contains an entry for this variant (Variation ID: 188304). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

0.13

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.61

D;.;.;.;.;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D;.;D;.;D

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.75

D;D;D;D;D;D

MetaSVM

Uncertain

0.31

MutationAssessor

Uncertain

2.2

M;.;.;.;.;M

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-4.0

D;D;.;.;.;D

REVEL

Uncertain

0.64

Sift

Uncertain

0.0070

D;D;.;.;.;D

Sift4G

Uncertain

0.0060

D;D;.;.;.;D

Polyphen

1.0

D;D;.;.;D;D

Vest4

0.84

MutPred

0.49

Loss of glycosylation at T156 (P = 0.0242);.;.;.;.;Loss of glycosylation at T156 (P = 0.0242);

MVP

0.88

MPC

0.26

ClinPred

0.96

GERP RS

4.5

Varity_R

0.62

gMVP

0.72

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