7-5973465-C-T

Position:

• chr7-5973465-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_Moderate PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:4
• Conservation: PhyloP100: 7.90

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 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. Fraction of 0.0255 CDS is truncated, and there are 0 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 id is 127786.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Pathogenic=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7	c.2523G>A	p.Trp841*	stop_gained	15/15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.2523G>A	p.Trp841*	stop_gained	15/15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes AF: 0.00166 AC: 130 AN: 78158 Hom.: 0 Cov.: 10

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

GnomAD3 exomes AF: 0.000393 AC: 71 AN: 180738 Hom.: 3 AF XY: 0.000327 AC XY: 32 AN XY: 97862

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 SAS 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.: 5 Cov.: 9 AF XY: 0.000151 AC XY: 56 AN XY: 371868

Gnomad4 AFR exome AF: 0.00650

Gnomad4 AMR exome AF: 0.000183

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: 0.00000429

Gnomad4 OTH exome AF: 0.000148

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00166 AC: 130 AN: 78246 Hom.: 0 Cov.: 10 AF XY: 0.00146 AC XY: 53 AN XY: 36180

Gnomad4 AFR AF: 0.00618

Gnomad4 AMR AF: 0.000584

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000925 Hom.: 0

ExAC AF: 0.000472 AC: 53

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Aug 27, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 11, 2023	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:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 25, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Hereditary nonpolyposis colon cancer Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jul 12, 2024

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

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

May 13, 2021

- -

PMS2-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 30, 2024

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	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
Vest4		0.80
GERP RS		5.3

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: rs587780057; hg19: chr7-6013096;