7-6009009-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_000535.7(PMS2):c.11C>G(p.Ala4Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000422 in 1,612,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:14

Conservation

PhyloP100: 0.740

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 Uncertain_significance. Variant got 2 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7 link	c.11C>G	p.Ala4Gly	missense_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.11C>G	p.Ala4Gly	missense_variant	Exon 1 of 15	1	NM_000535.7	ENSP00000265849.7		P54278-1

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250258

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135576

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000431

AC:

AN:

1460242

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

726436

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:

0.0000567

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000847

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:14

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PMS2: PM2:Supporting, PP3, PS3:Supporting, PS4:Supporting -

Apr 30, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 08, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with colon cancer which demonstrated normal immunohistochemistry or MLH1 hypermethylation, in unaffected controls, and in individual(s) with pancreatic cancer (PMID: 25479140, 28466842); In silico analysis supports a deleterious effect on splicing; In silico analysis supports that this missense variant does not alter protein structure/function; Located in the critical ATPase domain (PMID: 11574484); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25479140, 28466842, 11574484, 32133419) -

Jan 16, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM2 -

Lynch syndrome 4

Uncertain:4

Apr 19, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 04, 2023

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

Mar 22, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Hereditary cancer-predisposing syndrome

Pathogenic:1Uncertain:2

Jul 10, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.11C>G variant (also known as p.A4G), located in coding exon 1 of the PMS2 gene, results from a C to G substitution at nucleotide position 11. The alanine at codon 4 is replaced by glycine, an amino acid with similar properties. The p.A4G alteration was identified in an Icelandic colorectal cancer cohort in an individual with normal mismatch repair protein staining via immunohistochemistry (IHC) and in another individual with MLH1 promoter hypermethylation, but the nucleotide numbering for this variant was not provided (Haraldsdottir S et al. Nat Commun. 2017 05;8:14755). This alteration was also identified in an individual diagnosed with pancreatic cancer (Grant RC et al. Gastroenterology, 2015 Mar;148:556-64). Additionally, this variant was identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This alteration was also detected in a study of 1,165 individuals with a history of colorectal cancer or colon polyps as well as 590 controls (Gordon AS et al. Am J Hum Genet, 2019 09;105:526-533). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Aug 09, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces alanine with glycine at codon 4 of the PMS2 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may create an alternative splice donor site 13 basepair upstream of the reference splice donor site, which has been confirmed by an RNA study to affect some RNA transcripts (PMID: 32133419). The aberrant RNA transcript is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with colorectal cancer (PMID: 28466842). One of the tumors was found to have normal PMS2 protein expression via immunohistochemistry analysis, and another had MLH1 and PMS2 loss but also demonstrated hypermethylated MLH1 promoter. This tumor data suggests that PMS2 expression is not significantly disrupted. This variant has also been reported in individuals affected with colorectal cancer or colon polyps (PMID: 31422818), pancreatic cancer (PMID: 25479140), prostate cancer (PMID: 32832836), and breast cancer (PMID: 32133419, 33471991), as well as healthy individuals (PMID: 33471991). This variant has been identified in 3/250258 chromosomes in the general population by the Genome Aggregation Database (gnomAD). While the experimental data suggest that the variant may impact RNA splicing, the available clinical evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Jul 27, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not specified

Uncertain:1

Dec 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ala4Gly variant in PMS2 has not been previously reported in individuals wi th colorectal cancer, but has been identified in 1/11544 Latino chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs7 45361721). While computational pathogenicity prediction tools and conservation a nalysis suggest that the p.Ala4Gly variant may not impact the protein, this vari ant is predicted to create a novel splice site. However, the accuracy of these tools is unknown and therefore this information is not predictive enough to dete rmine or rule out pathogenicity. In summary, the clinical significance of the p. Ala4Gly variant is uncertain. -

Lynch syndrome

Uncertain:1

Aug 06, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces alanine with glycine at codon 4 of the PMS2 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may create an alternative splice donor site 13 basepair upstream of the reference splice donor site, which has been confirmed by an RNA study to affect some RNA transcripts (PMID: 32133419). The aberrant RNA transcript is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with colorectal cancer, although the individual was found to also have normal PMS2 protein expression and hypermethylated MLH1 promoter in the tumor (PMID: 28466842). The primary cause of disease in this individual is not clear. This variant has also been reported in individuals affected with pancreatic cancer (PMID: 25479140) and breast cancer (PMID: 32133419). This variant has been identified in 3/250258 chromosomes in the general population by the Genome Aggregation Database (gnomAD). While the experimental data suggest that the variant may impact RNA splicing, the available clinical evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hereditary nonpolyposis colorectal neoplasms

Uncertain:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 4 of the PMS2 protein (p.Ala4Gly). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs745361721, gnomAD 0.003%). This missense change has been observed in individual(s) with colorectal cancer and pancreatic cancer (PMID: 25479140, 28466842, 37937776). ClinVar contains an entry for this variant (Variation ID: 232589). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PMS2 protein function with a negative predictive value of 95%. Studies have shown that this missense change results in partial exon 1 deletion, and produces a non-functional protein and/or introduces a premature termination codon (internal data). 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. -

Malignant tumor of breast

Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PMS2 p.Ala4Gly variant was identified in the literature with carrier frequency in Iceland of 0.04 and odds ratio for CRC of 2.64 (95%CI:0.62-11.2, Haraldsdottir 2017). The variant was also identified in dbSNP (ID: rs745361721) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx and three other submitters), and in Insight Hereditary Tumors database (1x). The variant was not identified in COGR, MutDB, Zhejiang University Database, or Mismatch Repair Genes Variant Database. The variant was identified in control databases in 3 of 245352 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 33576 chromosomes (freq: 0.00003), European in 2 of 110948 chromosomes (freq: 0.00002), while the variant was not observed in the African, Other, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ala4 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

DANN

Benign

0.89

DEOGEN2

Benign

0.13

T;.

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.57

T;T

M_CAP

Benign

0.054

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

0.69

N;N

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.1

N;N

REVEL

Uncertain

0.48

Sift

Benign

0.038

D;D

Sift4G

Benign

0.18

T;T

Polyphen

0.17

B;B

Vest4

0.21

MutPred

0.042

Loss of glycosylation at S7 (P = 0.1402);Loss of glycosylation at S7 (P = 0.1402);

MVP

0.82

MPC

0.048

ClinPred

0.11

GERP RS

2.5

Varity_R

0.061

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.99

Position offset: 1

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