Variant 7-5995612-T-C details in Genebe, Genetics Data Aggregator

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:

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

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

PP5

Variant 7-5995612-T-C is Pathogenic according to our data. Variant chr7-5995612-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 232390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5995612-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7 linkuse as main transcript	c.825A>G	p.Gln275=	synonymous_variant	8/15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12 linkuse as main transcript	c.825A>G	p.Gln275=	synonymous_variant	8/15	1	NM_000535.7	ENSP00000265849	P3	P54278-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251422

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

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

AF:

0.00000205

AC:

AN:

1460892

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726826

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lynch syndrome 4

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 19, 2023	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data]. -
Likely pathogenic, no assertion criteria provided	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Oct 10, 2019	- -
Likely pathogenic, criteria provided, single submitter	research	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Dec 09, 2022	PS3, PS4_SUP, PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 05, 2024	- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 28, 2021	The c.825A>G pathogenic mutation (also known as p.Q275Q), located in coding exon 8, results from an A to G substitution at nucleotide position 825 of the PMS2 gene. This nucleotide substitution does not change the amino acid at codon 275. In one study, this alteration was detected in trans with a pathogenic PMS2 mutation in a patient diagnosed with rectal adenomatous polyps, cutaneous lentigines, and hyperpigmentation at age 24 whose family history included a sister with a brain tumor at age 11; these findings are consistent with constitutional mismatch repair deficiency (CMMR-D). RNA analysis of this variant showed abnormal splicing leading to premature protein truncation, and absence of PMS2 by immunohistochemistry was noted in the adenoma, brain tumor, and normal tissues from the proband and the affected sister (Johannesma PC et al. Clin. Genet. 2011 Sep;80:243-55). Additionally, a minigene assay of this variant showed out of frame skipping of the first 22 nucleotides of exon 8, and no full length transcript was produced from the variant allele (van der Klift HM et al. Mol Genet Genomic Med 2015 Jul;3:327-45). This alteration was also reported in conjunction with an alteration in MLH1 (p.Y684D) in a patient diagnosed with colon at 35 years old, belonged to an Amsterdam I family, and showed absent staining of MLH1/PMS2 on IHC (Martin-Morales L et al. PLoS ONE, 2018 Sep;13:e0203885). Of note, this alteration has also been reported in a patient with breast cancer diagnosed at age 52 (Goodenberger ML et al. Genet. Med. 2016 Jan;18:13-9). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 26, 2023	This synonymous variant causes a A>G nucleotide change in exon 8 of the PMS2 gene. Splice site prediction tools indicate that this variant creates a de novo splice acceptor site 22 nucleotides downstream of the native intron 7/exon 8 splice acceptor site. RNA studies in patient cells (PMID: 21261604) and by minigene analysis (PMID: 26247049) have shown that this variant results in use of the de novo acceptor site in exon 8, resulting in a 22 nucleotide deletion in the mRNA, causing a frameshift and protein truncation. Absence of PMS2 in patient cells by immunohistochemistry has been observed. (PMID: 21261604). This variant has been reported in individuals with phenotypes consistent with constitutional mismatch repair deficiency (CMMRD; PMID: 21261604). This variant has been identified in 2/251422 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Lynch syndrome 4;C5399763:Mismatch repair cancer syndrome 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Hereditary nonpolyposis colon cancer

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Mar 04, 2024

Variant summary: PMS2 c.825A>G alters a non-conserved nucleotide resulting in a synonymous change. Computational tools predict a significant impact on normal splicing: Three predict the variant creates a cryptic 3' acceptor site. Publications report experimental evidence that this variant affects mRNA splicing, resulting in a deletion of 22 nt (Johannesma_2011, van der Klift_2015). The variant allele was found at a frequency of 8e-06 in 251422 control chromosomes (gnomAD). c.825A>G has been reported in the literature in the compound heterozygous state with other pathogenic variants in individuals affected with features of constitutional mismatch repair deficiency (e.g. Johannesma_2011, Mishra_2022). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 21261604, 26247049, 35532657). ClinVar contains an entry for this variant (Variation ID: 232390). Based on the evidence outlined above, the variant was classified as pathogenic. -

Lynch syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 18, 2023

This synonymous variant causes a A>G nucleotide change in exon 8 of the PMS2 gene. Splice site prediction tools indicate that this variant creates a de novo splice acceptor site 22 nucleotides downstream of the native intron 7/exon 8 splice acceptor site. RNA studies in patient cells (PMID: 21261604) and by minigene analysis (PMID: 26247049) have shown that this variant results in use of the de novo acceptor site in exon 8, resulting in a 22 nucleotide deletion in the mRNA, causing a frameshift and protein truncation. Absence of PMS2 in patient cells by immunohistochemistry has been observed. (PMID: 21261604). This variant has been reported in individuals with phenotypes consistent with constitutional mismatch repair deficiency (CMMRD; PMID: 21261604). This variant has been identified in 2/251422 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Gastric cancer

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 09, 2024

This variant is associated with the following publications: (PMID: 30256826, 27435373, 25856668, 28514183, 30787465, 26110232, 30589920, 35477782, 34172528, 36988593, 35532657, 21261604, 26247049) -

Hereditary nonpolyposis colorectal neoplasms

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 21, 2023

This sequence change affects codon 275 of the PMS2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PMS2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has been observed in individual(s) with Lynch syndrome and symptoms consistent with constitutional mismatch repair deficiency (CMMR-D) (PMID: 21261604, 25856668, 26110232, 28514183). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 232390). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 26247049; Invitae). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

DANN

Benign

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.79

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.79

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.

7-5995612-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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