rs41534544

chr7-5987144-T-Cchr7-5987144-T-Gchr7-5987144-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000535.7(PMS2):c.1621A>G(p.Lys541Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.85 in 1,611,014 control chromosomes in the GnomAD database, including 584,176 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K541R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.87 (57167 hom., cov: 32)
  • Exomes 𝑓: 0.85 (527009 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15 O:1
• Conservation: PhyloP100: 1.50

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.4039015E-6).
• BP6: Variant 7-5987144-T-C is Benign according to our data. Variant chr7-5987144-T-C is described in ClinVar as [Benign]. Clinvar id is 135065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5987144-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.917 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.1621A>G	p.Lys541Glu	missense_variant	11/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.1621A>G	p.Lys541Glu	missense_variant	11/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes AF: 0.865 AC: 131537 AN: 151998 Hom.: 57124 Cov.: 32

Gnomad AFR AF: 0.925

Gnomad AMI AF: 0.938

Gnomad AMR AF: 0.772

Gnomad ASJ AF: 0.893

Gnomad EAS AF: 0.915

Gnomad SAS AF: 0.895

Gnomad FIN AF: 0.843

Gnomad MID AF: 0.899

Gnomad NFE AF: 0.845

Gnomad OTH AF: 0.855

GnomAD3 exomes AF: 0.841 AC: 210907 AN: 250846 Hom.: 89510 AF XY: 0.848 AC XY: 115081 AN XY: 135714

Gnomad AFR exome AF: 0.925

Gnomad AMR exome AF: 0.669

Gnomad ASJ exome AF: 0.889

Gnomad EAS exome AF: 0.921

Gnomad SAS exome AF: 0.895

Gnomad FIN exome AF: 0.839

Gnomad NFE exome AF: 0.850

Gnomad OTH exome AF: 0.840

GnomAD4 exome AF: 0.849 AC: 1238139 AN: 1458898 Hom.: 527009 Cov.: 51 AF XY: 0.851 AC XY: 617868 AN XY: 725902

Gnomad4 AFR exome AF: 0.930

Gnomad4 AMR exome AF: 0.681

Gnomad4 ASJ exome AF: 0.887

Gnomad4 EAS exome AF: 0.930

Gnomad4 SAS exome AF: 0.893

Gnomad4 FIN exome AF: 0.842

Gnomad4 NFE exome AF: 0.845

Gnomad4 OTH exome AF: 0.861

GnomAD4 genome AF: 0.865 AC: 131629 AN: 152116 Hom.: 57167 Cov.: 32 AF XY: 0.864 AC XY: 64262 AN XY: 74342

Gnomad4 AFR AF: 0.925

Gnomad4 AMR AF: 0.771

Gnomad4 ASJ AF: 0.893

Gnomad4 EAS AF: 0.914

Gnomad4 SAS AF: 0.895

Gnomad4 FIN AF: 0.843

Gnomad4 NFE AF: 0.845

Gnomad4 OTH AF: 0.857

Alfa AF: 0.854 Hom.: 73695

Bravo AF: 0.859

TwinsUK AF: 0.847 AC: 3141

ALSPAC AF: 0.834 AC: 3216

ESP6500AA AF: 0.918 AC: 4045

ESP6500EA AF: 0.846 AC: 7270

ExAC AF: 0.851 AC: 103334

Asia WGS AF: 0.891 AC: 3101 AN: 3478

EpiCase AF: 0.851

EpiControl AF: 0.850

ClinVar

Significance: Benign

Submissions summary: Benign:15 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9 Other:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 11, 2016	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Disclaimer: This variant has not undergone full assessment. The following are pr eliminary notes: Frequency -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Lynch syndrome 4 Benign:3

Benign, criteria provided, single submitter	clinical testing	IntelligeneCG	Aug 18, 2017	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Mismatch repair cancer syndrome 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Lynch syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	5.5
Dann	Benign	0.22
DEOGEN2	Benign	0.052	T;.;.;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.00058	N
LIST_S2	Benign	0.22	T;T;.;T;.
MetaRNN	Benign	0.0000014	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.9	N;.;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.76	N;N;.;.;.
REVEL	Benign	0.16
Sift	Benign	1.0	T;T;.;.;.
Sift4G	Benign	1.0	T;T;.;.;.
Polyphen		0.0	B;B;.;.;B
Vest4		0.049
MPC		0.045
ClinPred		0.0016	T
GERP RS		4.7
Varity_R		0.044
gMVP		0.15

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

Other links and lift over

dbSNP: rs2228006; hg19: chr7-6026775; COSMIC: COSV56223170;