chr7-6005942-G-A

Position:

chr7-6005942-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP3

The ENST00000265849.12(PMS2):c.113C>T(p.Ala38Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,610,778 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. A38E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

PMS2
ENST00000265849.12 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:11

Conservation

PhyloP100: 9.57

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.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 uncertain in ENST00000265849.12

PP3

MetaRNN computational evidence supports a deleterious effect, 0.751

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7 linkuse as main transcript	c.113C>T	p.Ala38Val	missense_variant	2/15	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.113C>T	p.Ala38Val	missense_variant	2/15	1	NM_000535.7	ENSP00000265849	P3	P54278-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000203

AC:

AN:

245784

Hom.:

AF XY:

0.00000745

AC XY:

AN XY:

134166

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000870

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:

0.00000909

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1458528

Hom.:

Cov.:

AF XY:

0.00000965

AC XY:

AN XY:

725592

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.000365

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000257

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer, glioma, papillary thyroid cancer, and pituitary adenoma (Lu et al., 2015; Cetani et al., 2019; Mio et al., 2021; Abdel-Razeq et al., 2022); This variant is associated with the following publications: (PMID: 26689913, 31486992, 33821390, 35402282, 11574484, 36243179) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 27, 2019	- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 24, 2023	The p.A38V variant (also known as c.113C>T), located in coding exon 2 of the PMS2 gene, results from a C to T substitution at nucleotide position 113. The alanine at codon 38 is replaced by valine, an amino acid with similar properties. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 30, 2023	This missense variant replaces alanine with valine at codon 38 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 been reported in individuals affected with low grade glioma, breast or thyroid cancers (PMID: 26689913, 33821390, 35402282) as well as unaffected individuals (PMID: 36243179). This variant has been identified in 5/245784 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. -

Lynch syndrome 4

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 11, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

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

Dec 07, 2021

- -

PMS2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 10, 2024

The PMS2 c.113C>T variant is predicted to result in the amino acid substitution p.Ala38Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/187605/?new_evidence=true). 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

Dec 18, 2023

This missense variant replaces alanine with valine at codon 38 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 been reported in individuals affected with low grade glioma, breast or thyroid cancers (PMID: 26689913, 33821390, 35402282) as well as unaffected individuals (PMID: 36243179). This variant has been identified in 5/245784 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

Jan 10, 2024

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 38 of the PMS2 protein (p.Ala38Val). This variant is present in population databases (rs148270248, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This missense change has been observed to co-occur in individuals with a different variant in PMS2 that has been determined to be pathogenic (Invitae), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 187605). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PMS2 protein function. 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. -

Lynch syndrome 4;C5436817:Mismatch repair cancer syndrome 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.53

D;.

Eigen

Uncertain

0.61

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.75

D;D

MetaSVM

Pathogenic

0.87

MutationAssessor

Benign

0.72

N;N

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.0

D;D

REVEL

Pathogenic

0.70

Sift

Benign

0.12

T;T

Sift4G

Pathogenic

0.0

D;T

Polyphen

1.0

D;D

Vest4

0.77

MVP

0.97

MPC

0.27

ClinPred

0.72

GERP RS

5.7

Varity_R

0.64

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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