rs587779333

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_001406875.1(PMS2):c.-674A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PMS2
NM_001406875.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 2.52

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:

AIMP2 (HGNC:20609): (aminoacyl tRNA synthetase complex interacting multifunctional protein 2) The protein encoded by this gene is part of the aminoacyl-tRNA synthetase complex, which contains nine different aminoacyl-tRNA synthetases and three non-enzymatic factors. The encoded protein is one of the non-enzymatic factors and is required for assembly and stability of the complex. [provided by RefSeq, May 2016]

AIMP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 7-6009019-T-A is Pathogenic according to our data. Variant chr7-6009019-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 142777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 15	ENST00000265849.12	NP_000526.2	P54278-1Q7Z3Q2B4DGM0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 15	1	NM_000535.7	ENSP00000265849.7		P54278-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

250222

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135572

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460242

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726424

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Feb 21, 2018

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Observed in an individual with a history of a Lynch syndrome-related cancer and/or polyps and with a second PMS2 variant in a pediatric patient suspected of having constitutional mismatch repair deficiency (CMMR-D) syndrome (Yurgelun 2015, Adam 2016); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 18602922, 27476653, 28152038, 25980754, 23709753, 27742654, 27064304, 28466842, 26895986, 21376568, 29625052, 30787465, 29752822) -

Apr 29, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Apr 13, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant results in the loss of the translation start codon of the PMS2 gene. Although functional studies have not been reported for this variant, this variant is expected to result in an absent or non-functional protein product. This variant has been reported in two individuals affected with PMS2-associated cancer or colorectal polyps (PMID: 25980754, 27476653) and in an individual affected with breast and ovarian cancer (PMID: 24130102). This variant has been identified in 1/250222 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Two different variants, c.1A>G and c.2T>A, that also disrupt the PMS2 translation start codon are known to be pathogenic (Clinvar variation ID: 91323 and 182809, respectively). Loss of PMS2 function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic. -

Apr 09, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M1? pathogenic mutation (also known as c.1A>T) is located in coding exon 1 of the PMS2 gene and results from an A to T substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). This mutation was identified in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome (Yurgelun MB et al. Gastroenterology 2015 Sep;149(3):604-13.e20) and in a cohort of Chinese breast cancer patients (Li JY et al. Int J Cancer 2019 01;144(2):281-289). This specific alteration has been reported in conjunction with PMS2 pathogenic mutations in individuals with constitutional mismatch repair deficiency (CMMR-D) phenotypes, although phase of the alterations was unknown (Adam R et al. Am J Hum Genet 2016 Aug;99(2):337-51; Ambry internal data). A similar alteration impacting the same nucleotide position (c.1A>G) has been reported in trans with a second pathogenic PMS2 mutation in three patients with CMMR-D who had absence of PMS2 staining observed in both tumor and normal tissues (Senter L et al. Gastroenterology 2008 Aug;135(2):419-28) and in an individual diagnosed with early-onset endometrial cancer demonstrating isolated loss of PMS2 by IHC analysis (Borràs E et al. J. Med. Genet. 2013 Aug;50:552-63). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Lynch syndrome

Pathogenic:1

Sep 13, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant results in the loss of the translation start codon of the PMS2 gene. Although functional studies have not been reported for this variant, this variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with Lynch syndrome-associated cancer or colorectal polyps (PMID: 25980754) and in individuals affected with breast and/or ovarian cancer (PMID: 24130102, 29752822). The variant has been observed with a second pathogenic PMS2 variant in individuals affected with clinical features of constitutional mismatch repair deficiency (PMID: 27476653, 30680046; ClinVar SCV000187260.9). In one of these individuals, the variants were confirmed in the compound heterozygous state, suggesting this variant is disease-causing (PMID: 30680046). This variant has been identified in 1/250222 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Two different variants, c.1A>G and c.2T>A, that also disrupt the PMS2 translation start codon are known to be pathogenic (Clinvar variation ID: 91323 and 182809, respectively). Loss of PMS2 function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic. -

Hereditary nonpolyposis colorectal neoplasms

Pathogenic:1

Jul 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the PMS2 mRNA. The next in-frame methionine is located at codon 136. This variant is present in population databases (rs587779333, gnomAD 0.0009%). Disruption of the initiator codon has been observed in individuals with clinical features of Lynch syndrome and constitutional mismatch repair deficiency syndrome (PMID: 18602922, 20487569, 23709753, 24130102, 25559809, 25980754, 27476653; Invitae). ClinVar contains an entry for this variant (Variation ID: 142777). For these reasons, this variant has been classified as Pathogenic. -

Endometrial carcinoma

Pathogenic:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Met1 (c.1A>T) variant in exon 1 of the PMS2 gene has not been reported in the literature nor previously identified by our laboratory. This variant did not show up in the databases (dbSNP, NHLBI Exome sequencing project (exome variant server), HGMD, LOVD, COSMIC, UMD, ClinVar, or BIC) and it is unknown if it may or may not be causative of the disorder. However it causes the loss of the start codon for exon 1. This residue has not been seen in mammals and computational analyses (PolyPhen2, SIFT, AlignGVGD) and it is unknown if this suggests a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of this variant cannot be determined with certainty at this time; however based upon the arguments described above, we find this variant to be PATHOGENIC. -

Lynch syndrome 4

Pathogenic:1

Sep 15, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant is located within the gene translation start codon (p.Met1?) and is predicted to result in abnormal protein translation. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 30680046, 27476653, 18602922]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.086

T;.

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.080

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Benign

-0.58

PROVEAN

Benign

-0.72

N;N

REVEL

Uncertain

0.52

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

0.14

T;T

Polyphen

0.030

B;B

Vest4

0.91

MutPred

0.99

Loss of glycosylation at S6 (P = 0.2727);Loss of glycosylation at S6 (P = 0.2727);

MVP

0.83

ClinPred

0.99

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.95

gMVP

0.47

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