rs886039646

Variant names:

• chr7-5973466-CA-C
• rs886039646
• NM_000535.7:c.2521delT

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_Very_Strong

The NM_000535.7(PMS2):​c.2521delT​(p.Trp841GlyfsTer10) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001554334: However studies have shown that the C-term of PMS2 is important for binding to MLH1 which is integral to PMS2 function (Kosinski 2010, Guerrette 1999)." and additional evidence is available in ClinVar. The gene PMS2 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: 𝑓 0.000038 (0 hom., cov: 10)
• Consequence: PMS2 NM_000535.7 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.32
• Publications: 6 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: Orphanet, ClinGen
• Lynch syndrome 4

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

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• 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

Specifications for PMS2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 21 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV001554334: However studies have shown that the C-term of PMS2 is important for binding to MLH1 which is integral to PMS2 function (Kosinski 2010, Guerrette 1999).; SCV000625623: Experimental studies have shown that this premature translational stop signal affects PMS2 function (PMID: 26116798). This variant disrupts the MLH1 interaction domain of the PMS2 protein, which has been shown to be critical for PMS2-MLH1 dimerization (PMID: 10037723), and therefore mismatch repair activity (PMID: 16338176, 20533529).; SCV000697352: "In functional studies performed on lymphoblastoid cell lines (LCLs) derived from the patient carrying the variant in homozygosity, MSI (microsatellite instability) and tolerance to methylating agents could be demonstrated (while these changes couldn't be shown in LCLs from MMR-proficient controls, including Lynch syndrome patients; Bodo 2015)."
• PP5: Variant 7-5973466-CA-C is Pathogenic according to our data. Variant chr7-5973466-CA-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 265586.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	NM_000535.7	MANE Select	c.2521delT	p.Trp841GlyfsTer10	frameshift	Exon 15 of 15	NP_000526.2	P54278-1
	PMS2	NM_001406866.1		c.2707delT	p.Trp903GlyfsTer10	frameshift	Exon 16 of 16	NP_001393795.1	A0A8V8TNX6
	PMS2	NM_001322014.2		c.2554delT	p.Trp852GlyfsTer10	frameshift	Exon 15 of 15	NP_001308943.1	A0A8V8TQ50

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	ENST00000265849.12	TSL:1 MANE Select	c.2521delT	p.Trp841GlyfsTer10	frameshift	Exon 15 of 15	ENSP00000265849.7	P54278-1
	PMS2	ENST00000382321.5	TSL:1	c.1318delT	p.Trp440GlyfsTer10	frameshift	Exon 11 of 11	ENSP00000371758.4	P54278-2
	PMS2	ENST00000406569.8	TSL:1	n.*162delT		non_coding_transcript_exon	Exon 13 of 13	ENSP00000514464.1	P54278-3

Frequencies

GnomAD3 genomes AF: 0.0000383 AC: 3 AN: 78260 Hom.: 0 Cov.: 10

Gnomad AFR AF: 0.0000981

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: 0.0000259

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 9

GnomAD4 genome AF: 0.0000383 AC: 3 AN: 78346 Hom.: 0 Cov.: 10 AF XY: 0.00 AC XY: 0 AN XY: 36188

African (AFR) AF: 0.0000978 AC: 2 AN: 20446

American (AMR) AF: 0.00 AC: 0 AN: 6882

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2086

East Asian (EAS) AF: 0.00 AC: 0 AN: 2372

South Asian (SAS) AF: 0.00 AC: 0 AN: 1848

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 172

European-Non Finnish (NFE) AF: 0.0000259 AC: 1 AN: 38666

Other (OTH) AF: 0.00 AC: 0 AN: 968

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Hereditary nonpolyposis colorectal neoplasms (1)
1	-	-	Lynch syndrome 4 (1)
1	-	-	Mismatch repair cancer syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3
Mutation Taster		=3/197	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs886039646;

hg19: chr7-6013097;