7-5973397-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000535.7(PMS2):c.*2C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. 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 0.0000088 (0 hom., cov: 19)
  • Exomes 𝑓: 0.0000073 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PMS2 NM_000535.7 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: -3.60

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 7-5973397-G-A is Benign according to our data. Variant chr7-5973397-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 187618.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.*2C>T		3_prime_UTR_variant	15/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.*2C>T		3_prime_UTR_variant	15/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes AF: 0.00000883 AC: 1 AN: 113238 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000321

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000501 AC: 1 AN: 199490 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 108602

Gnomad AFR exome AF: 0.0000873

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000728 AC: 6 AN: 824222 Hom.: 0 Cov.: 11 AF XY: 0.00000700 AC XY: 3 AN XY: 428388

Gnomad4 AFR exome AF: 0.0000481

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000321

Gnomad4 SAS exome AF: 0.0000152

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000355

Gnomad4 OTH exome AF: 0.0000263

GnomAD4 genome AF: 0.00000883 AC: 1 AN: 113294 Hom.: 0 Cov.: 19 AF XY: 0.0000185 AC XY: 1 AN XY: 53970

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000321

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 01, 2017	- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 25, 2015

The c.*2C>T variant is located in the 3' untranslated region (3’UTR) of the PMS2 gene. This variant results from a C to T substitution 2 nucleotides after the termination codon of the PMS2 gene. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 5971 samples (11942 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.003% (greater than 65000 alleles tested) in our clinical cohort. This nucleotide position is poorly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of c.*2C>T remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 24, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.011
Dann	Benign	0.77

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: rs764124442; hg19: chr7-6013028;