7-5973396-C-T

Variant summary

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

The NM_000535.7(PMS2):c.*3G>A 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 0.000087 (0 hom., cov: 19)
  • Exomes 𝑓: 0.000024 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: PMS2 NM_000535.7 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: -3.46

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=-0.91).
• BP6: Variant 7-5973396-C-T is Benign according to our data. Variant chr7-5973396-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 185828.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=1, Benign=1}. Variant chr7-5973396-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0000867 AC: 10 AN: 115298 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.000230

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000553

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000151 AC: 3 AN: 199080 Hom.: 1 AF XY: 0.0000277 AC XY: 3 AN XY: 108398

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: 0.0000345

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000244 AC: 20 AN: 818390 Hom.: 2 Cov.: 11 AF XY: 0.0000211 AC XY: 9 AN XY: 425600

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: 0.0000216

Gnomad4 NFE exome AF: 0.0000323

Gnomad4 OTH exome AF: 0.0000265

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000867 AC: 10 AN: 115298 Hom.: 0 Cov.: 19 AF XY: 0.000109 AC XY: 6 AN XY: 54944

Gnomad4 AFR AF: 0.000230

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000553

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 13, 2023	This variant is located in the 3' untranslated region of the PMS2 gene. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 5/219538 chromosomes in the general population by the Genome Aggregation Database (gnomAD). However, this observed allele frequency is not considered reliable since the gnomAD dataset does not disambiguate possible interference from homologous sequences in the PMS2CL pseudogene. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 06, 2017	The c.*3G>A variant is located in the 3' untranslated region (3’ UTR) of the PMS2 gene. This variant results from a G to A substitution 3 nucleotides downstream of the last translated codon. Based on nucleotide sequence alignment, this position is poorly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 16, 2020	Variant summary: PMS2 c.*3G>A is located in the untranslated mRNA region downstream of the termination codon. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.5e-05 in 199080 control chromosomes in the gnomAD database, including 1 homozygotes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.*3G>A in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 01, 2023	This variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000058 (1/17120 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.21
Dann	Benign	0.75

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: rs776493195; hg19: chr7-6013027;