7-6004059-C-G

Variant names:

• chr7-6004059-C-G
• rs763308607
• NM_000535.7:c.164-1G>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_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:11
• Conservation: PhyloP100: 5.46
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Lynch syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• mismatch repair cancer syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• ovarian cancer

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• Muir-Torre syndrome

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Y_RNA (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.03360371 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 186061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7	c.164-1G>C		splice_acceptor_variant, intron_variant	Intron 2 of 14	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.164-1G>C		splice_acceptor_variant, intron_variant	Intron 2 of 14	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248116 AF XY: 0.00000745

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.32e-7 AC: 1 AN: 1367028 Hom.: 0 Cov.: 23 AF XY: 0.00000146 AC XY: 1 AN XY: 685180

African (AFR) AF: 0.00 AC: 0 AN: 31468

American (AMR) AF: 0.00 AC: 0 AN: 44274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25504

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39226

South Asian (SAS) AF: 0.00 AC: 0 AN: 83200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3950

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1029014

Other (OTH) AF: 0.00 AC: 0 AN: 57052

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000267 Hom.: 0

Bravo AF: 0.00000378

Asia WGS AF: 0.000289 AC: 1 AN: 3474

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lynch syndrome 4 Pathogenic:5

Jan 28, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2020

Kong lab, Department of Laboratory Medicine, National Cancer Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The c.164-1G>C variant in PMS2 was detected in a patient diagnosed with breast cancer (IDC), HR-, HER2+ and gastric cancer at 47 years of age. Her father was diagnosed with colon cancer at 73 years old, while her uncle died of gastric cancer at age 60. The rest of the family was healthy. RT-PCR and sequencing analyses demonstrated that this variant led to 8-bp deletion in exon 3, causing a frameshift and generating a truncated PMS2 protein (Ryu et al., 2020; PMID: 32761968). This variant has been observed at very low frequency in population databases with allele frequencies of 7.0E-06 in gnomAD_genomes, 8.0E-06 in ExAC according to the most recent data from dbSNP (rs763308607). Given its impact on PMS2 function and its potential association with Lynch syndrome, PMS2 c.164-1G>C has been classified as likely pathogenic. -

Mar 09, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 17, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Apr 04, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Pathogenic:2

Jul 26, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 17, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 07, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 06, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 09, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 altered 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 PMS2-related conditions (PMID: 23709753, 25856668, 28514183, 31992580, 32761968). 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 produces a non-functional protein and/or introduces a premature termination codon (internal data). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		5.5
GERP RS		5.5
PromoterAI		0.0099	Neutral
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
Splicevardb		3.0
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

Other links and lift over

dbSNP: rs763308607; hg19: chr7-6043690; COSMIC: COSV99763916; COSMIC: COSV99763916;