NM_000535.7:c.2324A>G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_ModerateBP6_Very_Strong

The NM_000535.7(PMS2):​c.2324A>G​(p.Asn775Ser) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.0011 ( 2 hom., cov: 30)
Exomes 𝑓: 0.00027 ( 24 hom. )
Failed GnomAD Quality Control

Consequence

PMS2
NM_000535.7 missense

Scores

1
5
13

Clinical Significance

Benign reviewed by expert panel U:1B:26O:1

Conservation

PhyloP100: 4.85
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.15660042).
BP6
Variant 7-5977709-T-C is Benign according to our data. Variant chr7-5977709-T-C is described in ClinVar as [Benign]. Clinvar id is 36689.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-5977709-T-C is described in Lovd as [Likely_benign]. Variant chr7-5977709-T-C is described in Lovd as [Benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PMS2NM_000535.7 linkc.2324A>G p.Asn775Ser missense_variant Exon 14 of 15 ENST00000265849.12 NP_000526.2 P54278-1Q7Z3Q2B4DGM0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PMS2ENST00000265849.12 linkc.2324A>G p.Asn775Ser missense_variant Exon 14 of 15 1 NM_000535.7 ENSP00000265849.7 P54278-1

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
169
AN:
150216
Hom.:
2
Cov.:
30
FAILED QC
Gnomad AFR
AF:
0.000613
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00112
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000783
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000289
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00172
Gnomad OTH
AF:
0.00195
GnomAD3 exomes
AF:
0.000252
AC:
63
AN:
249826
Hom.:
3
AF XY:
0.000230
AC XY:
31
AN XY:
135022
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000377
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000984
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000382
Gnomad OTH exome
AF:
0.000656
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.000268
AC:
390
AN:
1452696
Hom.:
24
Cov.:
32
AF XY:
0.000263
AC XY:
190
AN XY:
722712
show subpopulations
Gnomad4 AFR exome
AF:
0.000150
Gnomad4 AMR exome
AF:
0.000314
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000101
Gnomad4 SAS exome
AF:
0.000105
Gnomad4 FIN exome
AF:
0.000151
Gnomad4 NFE exome
AF:
0.000302
Gnomad4 OTH exome
AF:
0.000233
GnomAD4 genome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00112
AC:
169
AN:
150318
Hom.:
2
Cov.:
30
AF XY:
0.00117
AC XY:
86
AN XY:
73352
show subpopulations
Gnomad4 AFR
AF:
0.000611
Gnomad4 AMR
AF:
0.00112
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000785
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000289
Gnomad4 NFE
AF:
0.00172
Gnomad4 OTH
AF:
0.00193
Alfa
AF:
0.000625
Hom.:
2
ExAC
AF:
0.000545
AC:
66
EpiCase
AF:
0.00132
EpiControl
AF:
0.000715

ClinVar

Significance: Benign
Submissions summary: Uncertain:1Benign:26Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Lynch syndrome 4 Benign:6
Jul 18, 2019
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

May 11, 2023
Myriad Genetics, Inc.
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Jan 22, 2016
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 13, 2017
Counsyl
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 31, 2017
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not specified Benign:5Other:1
Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Mayo Clinic Laboratories, Mayo Clinic
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 01, 2018
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 19, 2013
ITMI
Significance: not provided
Review Status: no classification provided
Collection Method: reference population

- -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Benign:4
-
Clinical Genetics, Academic Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 24, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 06, 2018
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22949387, 24728327, 22594646, 28347324) -

Dec 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PMS2: PP2, BS2 -

Hereditary cancer-predisposing syndrome Benign:4
Jul 23, 2014
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as 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. -

Apr 27, 2021
Sema4, Sema4
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Dec 16, 2014
Color Diagnostics, LLC DBA Color Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 27, 2021
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Lynch syndrome Uncertain:1Benign:2
Oct 30, 2015
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Significance: Uncertain significance
Review Status: flagged submission
Collection Method: clinical testing

- -

Feb 18, 2013
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 05, 2013
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Significance: Benign
Review Status: reviewed by expert panel
Collection Method: research

MAF >1% -

Breast and/or ovarian cancer Benign:1
Sep 13, 2022
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Lynch syndrome 4;C5399763:Mismatch repair cancer syndrome 1 Benign:1
Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Lynch syndrome 1 Benign:1
Jul 24, 2014
Pathway Genomics
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1
Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Endometrial carcinoma Benign:1
-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

PMS2, Exon14, c.2324A>G, p. Asn775Ser, Benign, ACMG 5 The c.2324A>G variant was identified in 32 of 1428 proband chromosomes (frequency: 0.022) from individuals or families with HNPCC or Lynch syndrome (20698049_sheng_2010, 14756672_Thompson_2004, Clendenning_2006_16619239); however, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. The variant was also identified in dbSNP (ID: rs17420802 ) “With benign allele”, HGMD, COSMIC, “Mismatch Repair Genes Variant Database”, “InSiGHT Colon Cancer Database”, and the ClinVar database by 7 submitters as benign. The p.Asn775 residue is conserved across mammals and lower organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Asn775Ser variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. The c.2324A>G variant occurs outside of the splicing consensus sequence and in silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) does not predict a difference in splicing in 5 of 5 different programs. (However, this information is not predictive enough to rule out pathogenicity.) In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.097
BayesDel_addAF
Benign
-0.051
T
BayesDel_noAF
Benign
-0.31
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.19
T;.;.;.;.;.
Eigen
Benign
-0.19
Eigen_PC
Benign
-0.022
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.88
D;D;.;D;.;D
M_CAP
Benign
0.025
T
MetaRNN
Benign
0.16
T;T;T;T;T;T
MetaSVM
Benign
-0.57
T
MutationAssessor
Benign
1.5
L;.;.;.;.;.
PrimateAI
Uncertain
0.66
T
PROVEAN
Uncertain
-3.1
D;D;.;.;.;D
REVEL
Uncertain
0.33
Sift
Benign
0.22
T;T;.;.;.;T
Sift4G
Benign
0.17
T;T;.;.;.;T
Polyphen
0.76
P;D;.;.;D;B
Vest4
0.39
MVP
0.82
MPC
2.1
ClinPred
0.20
T
GERP RS
4.6
Varity_R
0.35
gMVP
0.37

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs17420802; hg19: chr7-6017340; COSMIC: COSV56224196; API