7-5973465-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1PP5

The NM_000535.7(PMS2):c.2523G>A(p.Trp841*) variant causes a stop gained change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 10)

Exomes 𝑓: 0.00019 ( 5 hom. )

Failed GnomAD Quality Control

Consequence

PMS2
NM_000535.7 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:4

Conservation

PhyloP100: 7.90

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

Lynch syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Lynch syndrome 4
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
mismatch repair cancer syndrome 1
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
mismatch repair cancer syndrome 4
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
malignant pancreatic neoplasm
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
ovarian cancer
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
Muir-Torre syndrome
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
rhabdomyosarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
breast cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
prostate cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

PMS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 20 pathogenic variants in the truncated region.

PP5

Variant 7-5973465-C-T is Pathogenic according to our data. Variant chr7-5973465-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127786.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7 link	c.2523G>A	p.Trp841*	stop_gained	Exon 15 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.2523G>A	p.Trp841*	stop_gained	Exon 15 of 15	1	NM_000535.7	ENSP00000265849.7		P54278-1

Frequencies

GnomAD3 genomes

AF:

0.00166

AC:

130

AN:

78158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00620

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000585

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000393

AC:

AN:

180738

AF XY:

0.000327

show subpopulations

Gnomad AFR exome

AF:

0.00602

Gnomad AMR exome

AF:

0.000198

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000211

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000190

AC:

135

AN:

710508

Hom.:

Cov.:

AF XY:

0.000151

AC XY:

AN XY:

371868

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00650

AC:

122

AN:

18770

American (AMR)

AF:

0.000183

AC:

AN:

32804

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18844

East Asian (EAS)

AF:

0.00

AC:

AN:

29462

South Asian (SAS)

AF:

0.00

AC:

AN:

62728

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45272

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2584

European-Non Finnish (NFE)

AF:

0.00000429

AC:

AN:

466300

Other (OTH)

AF:

0.000148

AC:

AN:

33744

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.397

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00166

AC:

130

AN:

78246

Hom.:

Cov.:

AF XY:

0.00146

AC XY:

AN XY:

36180

show subpopulations

African (AFR)

AF:

0.00618

AC:

126

AN:

20380

American (AMR)

AF:

0.000584

AC:

AN:

6846

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2092

East Asian (EAS)

AF:

0.00

AC:

AN:

2376

South Asian (SAS)

AF:

0.00

AC:

AN:

1850

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4338

Middle Eastern (MID)

AF:

0.00

AC:

AN:

168

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

38694

Other (OTH)

AF:

0.00

AC:

AN:

966

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.405

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000925

Hom.:

ExAC

AF:

0.000472

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:1Uncertain:1

Aug 27, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Apr 11, 2023

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.W841* pathogenic mutation (also known as c.2523G>A), located in coding exon 15 of the PMS2 gene, results from a G to A substitution at nucleotide position 2523. This changes the amino acid from a tryptophan to a stop codon within coding exon 15. This alteration occurs at the 3' terminus of PMS2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 22 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data; Kosinski J et al. J. Mol. Biol., 2008 Oct;382:610-27). This alteration has been identified by multigene panel testing for hereditary cancer in a patient with male breast cancer and in a female patient diagnosed with breast cancer at the age of 41 who had a family history of breast and prostate cancer (Castéra L et al. Eur. J. Hum. Genet., 2014 Nov;22:1305-13; Fostira F et al. Breast Cancer Res. Treat., 2018 May;169:105-113). Another truncating pathogenic mutation located downstream from this alteration, p.W841Gfs*10, has also been identified in several individuals whose colorectal tumors demonstrated isolated loss of PMS2 expression on immunohistochemistry (IHC) (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Lynch syndrome 4

Pathogenic:1Uncertain:1

Sep 25, 2023

Myriad Genetics, Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

May 28, 2019

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary nonpolyposis colon cancer

Pathogenic:1

Jul 12, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PMS2 c.2523G>A (p.Trp841X) results in a premature termination codon in the last exon of the PMS2 mRNA, which raises the possibility of it escaping nonsense mediated decay and causing a truncation of the last 22 amino acids of the PMS2 protein, which might affect the MLH1 dimerization domain (PMID 10037723). This region also contains conserved residues that are predicted to be functionally important for metal ion binding, and appear required for normal MMR activity in mutation assays (PMID 18619468). Additionally, other variants downstream have been classified on the pathogenic spectrum internally and in ClinVar. The c.2523G>A (p.Trp841X) allele was found at a frequency of 0.00039 in 180738 control chromosomes, predominantly at a frequency of 0.006 within the African or African-American subpopulation in the gnomAD database, including 3 homozygotes. However, the region is highly homologous to PMS2 pseudogenes, and the technology utilized for this dataset does not rule out pseudogene interference, therefore these data might not be reliable for assessing variant frequency. c.2523G>A has been reported in the literature in individuals affected with HBOC and other tumor phenotypes (e.g. Castera_2014, Lu_2015, Fostira_2018, Guindalini_2022). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Of note however, in functional studies performed on lymphoblastoid cell lines (LCLs) derived from a patient carrying a similar truncating variant (c.2521delT (p.Trp841GlyfsX10)) in homozygosity, MSI (microsatellite instability) and tolerance to methylating agents could be demonstrated (PMID: 26116798). These results suggest that truncation of the last 22 amino acids might have functional importance. The following publications have been ascertained in the context of this evaluation (PMID: 24549055, 26689913, 29335925, 35264596). ClinVar contains an entry for this variant (Variation ID: 127786). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not specified

Uncertain:1

May 13, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PMS2-related disorder

Uncertain:1

Apr 30, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PMS2 c.2523G>A variant is predicted to result in premature protein termination (p.Trp841*). This variant was reported in multiple breast and ovarian cancer cohort studies (Castéra et al. 2014. PubMed ID: 24549055; Supplementary Data 2, Lu et al. 2015. PubMed ID: 26689913; Fostira et al. 2018. PubMed ID: 29335925). This variant is reported in 0.64% of alleles in individuals of African descent in gnomAD; however, this variant falls within a highly paralogous region and therefore allele frequency data should be interpreted with caution. This variant is interpreted as uncertain or pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127786). This variant resides in the final exon of this gene, and it is unclear if the resulting mRNA would undergo nonsense-mediated decay. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.66

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.98

PhyloP100

7.9

Vest4

0.80

GERP RS

5.3

Mutation Taster

=3/197

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over