7-6004059-C-G

Position:

chr7-6004059-C-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_000535.7(PMS2):c.164-1G>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000000732 in 1,367,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

PMS2
NM_000535.7 splice_acceptor, intron

Scores

Splicing: ADA: 0.9999

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 5.46

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 links:

PMS2 (HGNC:):

PMS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.03321746 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.9, offset of 8, new splice context is: taaactttctacatctaaAGctt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-6004059-C-G is Pathogenic according to our data. Variant chr7-6004059-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 186061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7 linkuse as main transcript	c.164-1G>C		splice_acceptor_variant, intron_variant		ENST00000265849.12	NP_000526.2	P54278-1Q7Z3Q2B4DGM0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12 linkuse as main transcript	c.164-1G>C		splice_acceptor_variant, intron_variant		1	NM_000535.7	ENSP00000265849.7		P54278-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000403

AC:

AN:

248116

Hom.:

AF XY:

0.00000745

AC XY:

AN XY:

134308

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

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:

7.32e-7

AC:

AN:

1367028

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

685180

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000255

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.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

Asia WGS

AF:

0.000289

AC:

AN:

3474

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lynch syndrome 4

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 17, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 04, 2023	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 09, 2022	- -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 26, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2024	Canonical splice site variant predicted to disrupt splicing in a gene for which loss of function is a known mechanism of disease; Published RNA studies suggest this variant results in use of a cryptic splice site and an aberrant transcript which is predicted to lead to a frameshift (PMID: 32761968); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25856668, 11574484, 34172528, 32761968, 31802016, 31992580) -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 07, 2023	This variant causes a G to C nucleotide substitution at the -1 position of intron 2 of the PMS2 gene. Functional RNA studies have shown that this variant causes a partial deletion of exon 3, resulting in premature truncation (PMID: 32761968). This variant has been reported in individuals affected with Lynch syndrome (PMID: 25856668, 31992580; ClinVar SCV000216319.6, SCV000572224.5). This variant has been identified in 1/248116 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 06, 2024	The c.164-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 3 of the PMS2 gene. This variant has been identified in probands whose Lynch syndrome-associated tumor demonstrated high microsatellite instability and/or loss of PMS2 expression by immunohistochemistry (IHC; Li S et al. J. Med. Genet. 2020 Jan;57:62-69; Ambry internal data). This alteration was also detected in an individual diagnosed with colorectal cancer at 45, and an individual diagnosed with endometrial cancer at 55 with demonstrated high microsatellite instability; however, the IHC results for the endometrial cancer demonstrated loss of MSH6 expression and were non-interpretable for PMS2 (Goodenberger ML et al. Genet Med, 2016 Jan;18:13-9; Wang Q et al. J Med Genet, 2020 07;57:487-499). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and 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). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

Lynch syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jul 09, 2023

The c.164-1G>C variant in the PMS2 gene is located at the canonical splice site of intron 2 and is predicted to cause alternative splicing, resulting in an absent or disrupted protein product. Experimental study of mRNA transcripts from patient samples showed partial deletion of exon 3 and truncated protein (PMID: 32761968). The variant has been reported in multiple individuals with Lynch syndrome-associated cancers (PMID: 31992580, 28514183, 32761968, 34793666, 30376427). Loss-of-function variants in PMS2 are known to be pathogenic for Lynch syndrome (PMID: 28514183, 25512458, 35223509). The variant is reported in ClinVar (ID: 186061). The variant is rare in the general population according to gnomAD (1/248116). Therefore, the c.164-1G>C variant of PMS2 has been classified as pathogenic. -

Hereditary nonpolyposis colorectal neoplasms

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 23, 2023

This sequence change affects an acceptor splice site in intron 2 of the PMS2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs763308607, gnomAD 0.006%). Disruption of this splice site has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 25856668, 31992580). ClinVar contains an entry for this variant (Variation ID: 186061). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.99

GERP RS

5.5

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.99

Position offset: -9

DS_AL_spliceai

0.64

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over