7-5992045-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PP3_Moderate

The NM_000535.7(PMS2):c.916G>A(p.Val306Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000127 in 1,577,524 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V306E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:1

Conservation

PhyloP100: 7.42

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

Lynch syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Lynch syndrome 4
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
mismatch repair cancer syndrome 1
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
mismatch repair cancer syndrome 4
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
malignant pancreatic neoplasm
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
ovarian cancer
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
Muir-Torre syndrome
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
rhabdomyosarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
breast cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
prostate cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

PMS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 58 uncertain in NM_000535.7

PP3

MetaRNN computational evidence supports a deleterious effect, 0.851

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7 link	c.916G>A	p.Val306Met	missense_variant	Exon 9 of 15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12 link	c.916G>A	p.Val306Met	missense_variant	Exon 9 of 15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

251148

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000105

AC:

AN:

1425480

Hom.:

Cov.:

AF XY:

0.00000984

AC XY:

AN XY:

711478

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32764

American (AMR)

AF:

0.0000224

AC:

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25930

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39534

South Asian (SAS)

AF:

0.00

AC:

AN:

85548

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53204

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

0.0000120

AC:

AN:

1079086

Other (OTH)

AF:

0.00

AC:

AN:

59052

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152044

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74252

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41392

American (AMR)

AF:

0.000328

AC:

AN:

15232

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.535

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000267

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Oct 17, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The PMS2 c.916G>A (p.Val306Met) variant has been reported in the published literature in individuals affected with colorectal cancer (PMIDs: 29596542 (2018), 30521064 (2019), 32661327 (2020)), breast cancer (PMIDs: 34326862 (2021), 35449176 (2022)), and an unspecified Lynch syndrome-associated cancer (PMID: 31391288 (2020)). This variant has also been observed in reportedly healthy individuals (PMIDs: 32980694 (2020), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared), 36243179 (2022)). The frequency of this variant in the general population, 0.000021 (6/282508 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. -

Apr 08, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with colorectal or breast cancer in the published literature (PMID: 29596542, 30521064, 35449176); This variant is associated with the following publications: (PMID: 30521064, 29596542, 32980694, 35449176, 11574484, 36243179) -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Jul 31, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces valine with methionine at codon 306 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 an individual affected with colorectal cancer (PMID: 30521064) and an individual affected with an unspecified cancer (PMID: 31391288). It was also found in control individuals from large breast and pancreatic cancer case-control studies (PMID: 32980694, 33471991). This variant has been identified in 6/282508 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. -

Nov 23, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

PMS2-related disorder

Uncertain:1

May 15, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PMS2 c.916G>A variant is predicted to result in the amino acid substitution p.Val306Met. This variant has been reported in an individual with colorectal cancer, non-polyposis (Table e2, Jiang et al. 2019. PubMed ID: 30521064), as well as in a patient with colorectal cancer in which the variant was not expected to have been the cause of disease (S Table 2. Hampel et al. 2018. PubMed ID: 29596542). In a breast cancer risk study, this variant was seen in zero breast cancer cases and in three control cases (Breast Cancer Association Consortium et al. 2021. PubMed ID: 33471991). This variant is reported in 0.0056% of alleles in individuals of Latino descent in gnomAD and is classified as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127801/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Lynch syndrome 1

Uncertain:1

Ding PR Lab, Sun Yat-sen University Cancer Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Lynch syndrome

Uncertain:1

Aug 13, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary nonpolyposis colorectal neoplasms

Uncertain:1

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 306 of the PMS2 protein (p.Val306Met). This variant is present in population databases (rs587780063, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 30521064, 31391288, 32661327, 34326862). ClinVar contains an entry for this variant (Variation ID: 127801). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt PMS2 function with a negative predictive value of 95%. 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

Uncertain:1

Aug 30, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.44

T;.;.;.;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;.;D;.

M_CAP

Benign

0.073

MetaRNN

Pathogenic

0.85

D;D;D;D;D

MetaSVM

Uncertain

0.56

MutationAssessor

Uncertain

2.9

M;.;.;.;.

PhyloP100

7.4

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-2.1

N;N;.;.;.

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0070

D;D;.;.;.

Sift4G

Benign

0.19

T;T;.;.;.

Polyphen

1.0

D;D;.;.;D

Vest4

0.86

MutPred

0.72

Gain of catalytic residue at V302 (P = 0.0192);.;.;.;.;

MVP

0.92

MPC

0.27

ClinPred

0.75

GERP RS

5.4

Varity_R

0.66

gMVP

0.59

Mutation Taster

=27/73

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over