chr7-5995607-G-T

Position:

chr7-5995607-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_000535.7(PMS2):c.830C>A(p.Thr277Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000239 in 1,613,328 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T277T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:14

Conservation

PhyloP100: 3.75

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011967629).

BP6

Variant 7-5995607-G-T is Benign according to our data. Variant chr7-5995607-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135946.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=3, Benign=6}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7 linkuse as main transcript	c.830C>A	p.Thr277Lys	missense_variant	8/15	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.830C>A	p.Thr277Lys	missense_variant	8/15	1	NM_000535.7	ENSP00000265849.7		P54278-1

Frequencies

GnomAD3 genomes

AF:

0.00130

AC:

198

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00449

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:

0.00633

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000278

AC:

AN:

251422

Hom.:

AF XY:

0.000199

AC XY:

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.00419

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000120

AC:

175

AN:

1461082

Hom.:

Cov.:

AF XY:

0.000103

AC XY:

AN XY:

726940

show subpopulations

Gnomad4 AFR exome

AF:

0.00412

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.000431

GnomAD4 genome

AF:

0.00138

AC:

210

AN:

152246

Hom.:

Cov.:

AF XY:

0.00152

AC XY:

113

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.00476

Gnomad4 AMR

AF:

0.000328

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000168

Hom.:

Bravo

AF:

0.00147

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000387

AC:

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:14

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 01, 2016	Variant summary: The c.830C>A variant affects a conserved nucleotide, resulting in amino acid change from Thr to Lys. 3/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). 4/5 programs in Alamut predict that this variant does not affect normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions are not confirmed by experimental studies. Sequence comparison suggests exon 8 does not match to any pseudogene region with high homology. This variant is found predominantly in African population at a frequency of 0.0045 (46/10332), which is about 39 times of maximal expected frequency of a pathogenic allele (0.0001136), suggesting this variant is benign. In addition, multiple clinical laboratories/literature classified this variant as benign. Taken together, this variant was classified as benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 11, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2020	This variant is associated with the following publications: (PMID: 25372392, 21153778, 22949387) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	PMS2: BP4, BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 09, 2022	BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 28, 2022	The PMS2 c.830C>A; p.Thr277Lys variant (rs1805322) is reported as benign/likely benign by multiple laboratories in ClinVar (Variation ID: 135946). This variant is found in the African population with an allele frequency of 0.5% (114/24962 alleles) in the Genome Aggregation Database. The threonine at codon 277 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.251). Although the evidence suggests this variant may be likely benign, there is currently insufficient information to classify with certainty. Therefore, based on available information, the clinical significance of this variant is uncertain at this time. -

Hereditary cancer-predisposing syndrome

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 03, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Aug 20, 2024	The variant is observed in one or more well-documented healthy adults. The p.Thr277Lys variant is observed in 68/16,248 (0.4185%) alleles from individuals of gnomAD African background in gnomAD, which is greater than expected for the disorder. There is a moderate physicochemical difference between threonine and lysine. For these reasons, this variant has been classified as Benign. -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Sep 29, 2017	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Breast and/or ovarian cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Nov 22, 2022

- -

Mismatch repair cancer syndrome 4

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 29, 2024

- -

Lynch syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 23, 2024

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Benign

0.71

DEOGEN2

Benign

0.19

T;.;.;.;.

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.16

LIST_S2

Uncertain

0.87

D;D;.;D;.

M_CAP

Benign

0.037

MetaRNN

Benign

0.012

T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.5

L;.;.;.;.

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.62

N;N;.;.;.

REVEL

Benign

0.25

Sift

Benign

0.93

T;T;.;.;.

Sift4G

Benign

0.51

T;T;.;.;.

Polyphen

0.30

B;B;.;.;B

Vest4

0.29

MVP

0.88

MPC

0.042

ClinPred

0.016

GERP RS

3.9

Varity_R

0.082

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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