7-5978605-C-T

Position:

chr7-5978605-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000535.7(PMS2):c.2266G>A(p.Asp756Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000466 in 150,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000095 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 2.93

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 -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21002036).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7 linkuse as main transcript	c.2266G>A	p.Asp756Asn	missense_variant	13/15	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.2266G>A	p.Asp756Asn	missense_variant	13/15	1	NM_000535.7	ENSP00000265849.7		P54278-1

Frequencies

GnomAD3 genomes

AF:

0.0000466

AC:

AN:

150306

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000738

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:

0.0000592

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000361

AC:

AN:

249312

Hom.:

AF XY:

0.0000297

AC XY:

AN XY:

134784

show subpopulations

Gnomad AFR exome

AF:

0.0000621

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000547

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000534

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000945

AC:

137

AN:

1448994

Hom.:

Cov.:

AF XY:

0.0000999

AC XY:

AN XY:

720870

show subpopulations

Gnomad4 AFR exome

AF:

0.0000303

Gnomad4 AMR exome

AF:

0.0000224

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:

0.000121

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000466

AC:

AN:

150306

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73312

show subpopulations

Gnomad4 AFR

AF:

0.0000738

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:

0.0000592

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 02, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: Fukui2011[Chapter], 26483394, 30306255) -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 16, 2022	This missense variant replaces aspartic acid with asparagine at codon 756 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 hereditary cancer in the literature. This variant has been identified in 9/244274 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. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 05, 2024	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

May 24, 2021

Variant summary: PMS2 c.2266G>A (p.Asp756Asn) results in a conservative amino acid change located in the MutL, C-terminal dimerization domain (IPR014790) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 249312 control chromosomes. 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.2266G>A 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. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary nonpolyposis colorectal neoplasms

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 05, 2024

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 756 of the PMS2 protein (p.Asp756Asn). 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: 234439). 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

Feb 10, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

T;.;.;.;.;.

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.93

D;D;.;D;.;D

M_CAP

Benign

0.059

MetaRNN

Benign

0.21

T;T;T;T;T;T

MetaSVM

Benign

-0.46

MutationAssessor

Benign

1.5

L;.;.;.;.;.

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-3.0

D;D;.;.;.;D

REVEL

Benign

0.22

Sift

Benign

0.15

T;T;.;.;.;T

Sift4G

Benign

0.28

T;T;.;.;.;T

Polyphen

0.024

B;D;.;.;D;B

Vest4

0.40

MVP

0.83

MPC

2.0

ClinPred

0.11

GERP RS

3.9

Varity_R

0.29

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