rs547715146

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000535.7(PMS2):c.2412G>C(p.Lys804Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000189 in 1,591,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K804R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 30)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: -0.131

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20136252).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7 linkuse as main transcript	c.2412G>C	p.Lys804Asn	missense_variant	14/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12 linkuse as main transcript	c.2412G>C	p.Lys804Asn	missense_variant	14/15	1	NM_000535.7	P3	P54278-1

Frequencies

GnomAD3 genomes

AF:

0.0000134

AC:

AN:

149382

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000298

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.94e-7

AC:

AN:

1441836

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

717542

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:

9.13e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000134

AC:

AN:

149484

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

72810

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000298

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 02, 2023	This missense variant replaces lysine with asparagine at codon 804 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 not been reported in individuals affected with PMS2-related disorders in the literature. This variant has not been identified 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. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 24, 2023	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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 28, 2019

Variant summary: PMS2 c.2412G>C (p.Lys804Asn) results in a non-conservative amino acid change located in the MutL, 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 was absent in 221484 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2412G>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 14, 2016

This variant is denoted PMS2 c.2412G>C at the cDNA level, p.Lys804Asn (K804N) at the protein level, and results in the change of a Lysine to an Asparagine (AAG>AAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Lys804Asn was not observed in approximately 5,700 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, and was not observed at significant allele frequency in 1000 Genomes. Since Lysine and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. PMS2 Lys804Asn occurs at a position where amino acids with properties similar to Lysine are tolerated across species and is located within the nuclease domain (Fukui 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether PMS2 Lys804Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Hereditary nonpolyposis colorectal neoplasms

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 15, 2023

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 804 of the PMS2 protein (p.Lys804Asn). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 142572). 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 not expected to disrupt PMS2 protein function with a negative 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. -

Lynch syndrome 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 20, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

T;.;.;.;.;.

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.62

LIST_S2

Uncertain

0.95

D;D;.;D;.;D

M_CAP

Benign

0.077

MetaRNN

Benign

0.20

T;T;T;T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.81

L;.;.;.;.;.

MutationTaster

Benign

0.75

D;N;N;N

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.8

N;N;.;.;.;N

REVEL

Benign

0.10

Sift

Uncertain

0.0030

D;D;.;.;.;D

Sift4G

Uncertain

0.0050

D;D;.;.;.;D

Polyphen

0.0010

B;B;.;.;B;B

Vest4

0.47

MutPred

0.57

Loss of methylation at K804 (P = 0.0332);.;.;.;.;.;

MVP

0.67

MPC

2.4

ClinPred

0.82

GERP RS

-0.40

Varity_R

0.47

gMVP

0.70

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