chr7-5997321-C-T

Variant names:

• chr7-5997321-C-T
• rs939641251
• NM_000535.7:c.803+5G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000535.7(PMS2):​c.803+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00000661 in 151,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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: 𝑓 0.0000066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PMS2 NM_000535.7 splice_region, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 4.81
• Publications: 0 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

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-5997321-C-T is Pathogenic according to our data. Variant chr7-5997321-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 486041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000535.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	NM_000535.7	MANE Select	c.803+5G>A		splice_region intron	N/A	NP_000526.2
	PMS2	NM_001406866.1		c.989+5G>A		splice_region intron	N/A	NP_001393795.1
	PMS2	NM_001322014.2		c.803+5G>A		splice_region intron	N/A	NP_001308943.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	ENST00000265849.12	TSL:1 MANE Select	c.803+5G>A		splice_region intron	N/A	ENSP00000265849.7
	PMS2	ENST00000382321.5	TSL:1	c.803+5G>A		splice_region intron	N/A	ENSP00000371758.4
	PMS2	ENST00000406569.8	TSL:1	n.803+5G>A		splice_region intron	N/A	ENSP00000514464.1

Frequencies

GnomAD3 genomes AF: 0.00000661 AC: 1 AN: 151364 Hom.: 0 Cov.: 30

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1251602 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 633002

African (AFR) AF: 0.00 AC: 0 AN: 29298

American (AMR) AF: 0.00 AC: 0 AN: 44114

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24666

East Asian (EAS) AF: 0.00 AC: 0 AN: 38556

South Asian (SAS) AF: 0.00 AC: 0 AN: 81544

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5370

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 921488

Other (OTH) AF: 0.00 AC: 0 AN: 53410

GnomAD4 genome AF: 0.00000661 AC: 1 AN: 151364 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 73844

African (AFR) AF: 0.00 AC: 0 AN: 41172

American (AMR) AF: 0.00 AC: 0 AN: 15122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67946

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000267 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lynch syndrome Pathogenic:2

Aug 31, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.803+5G>A variant in the PMS2 gene is located at the canonical splice site of intron 7 and is predicted to inflict donor loss (SpliceAI delta score: 0.98), resulting in alternative splicing and disrupted protein product. The variant has been reported in individuals with colorectal/endometrial/ovarian cancer (PMID: 31992580, 38311346). Patient peripheral blood RNA RT-PCR analysis demonstrated aberrant transcripts with either partial deletion or out-of-frame skipping of exon 7 (PMID: 38311346). Other splice variants located in the same splice junction (c.803+1G>T, c.803+1G>A) have also been reported from individuals with colorectal/endometrial cancer (PMID: 3501477, 36091691, 862267). Loss-of-function variants in the PMS2 gene are known to be pathogenic (PMID: 28514183, 25512458, 35223509). This variant has been reported in ClinVar (ID: 486041). This variant is absent in the general population according to gnomAD (v4.1). Therefore, the c.803+5G>A variant in the PMS2 gene is classified as likely pathogenic.

Sep 30, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.803+5G>A variant in PMS2 has been reported in at least 5 individuals with lynch syndrome-associated cancers (Karam 2019 PMID:31642931, Wang 2020 PMID:31992580, Ambry data). In addition, tumors sampled from 2 of these individuals showed either high microsatellite instability or lacked PMS2 expression (Wang 2020 PMID:31992580). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 486041) and has also been identified in 0.001% (1/67946) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, gnomAD v3.1.1). This variant is located in the 5' splice region and computational tools predict an impact to splicing. In vitro studies on patient RNA have shown that this variant results in abnormal splicing (Karam 2019 PMID:31642931). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PS4_Moderate, PS3_Moderate, PM2_Supporting, PP3.

Hereditary cancer-predisposing syndrome Pathogenic:2

Sep 11, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.803+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 7 in the PMS2 gene. This alteration was identified as germline in conjunction with a pathogenic PMS2 somatic mutation in an individual with colorectal cancer that displayed high microsatellite instability (MSI-H) and loss of PMS2 on immunohistochemistry (IHC), but no MLH1 promoter hypermethylation was detected (Ambry internal data). Furthermore, in this family, c.803+5G>A segregated with disease in a sibling diagnosed with endometrial cancer that demonstrated loss of PMS2 on IHC (Ambry internal data). This alteration was also identified in two French patients, one with endometrial cancer that was MSI-H and the other with colorectal cancer that was MSI-H and also demonstrated loss of PMS2 on IHC (Wang Q et al. J Med Genet, 2020 07;57:487-499). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Dec 17, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a G>A nucleotide substitution at the +5 position of intron 7 of the PMS2 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing, resulting in absent or disrupted protein product. RNA analysis done with patient RNA have demonstrated this variant results in two aberrant transcripts, with either an in-frame deletion or out-of-frame skipping of exon 7 (PMID: 32849802, 38311346). This variant has been reported in individuals and families affected with Lynch syndrome-associated tumors, with tumor data demonstrating high microsatellite instability and/or loss or PMS2 protein via immunohistochemistry (PMID: 31992580, 38311346; ClinVar SCV000674231.6, SCV000751167.5). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 7 of the PMS2 gene. It does not directly change the encoded amino acid sequence of the PMS2 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with PMS2-related conditions (PMID: 31992580; external communication, internal data). ClinVar contains an entry for this variant (Variation ID: 486041). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in multiple RNA products (internal data). 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	23
DANN	Benign	0.97
PhyloP100		4.8
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs939641251; hg19: chr7-6036952;