7-5986763-T-C

Variant names:

• chr7-5986763-T-C
• rs869320619
• NM_000535.7:c.2002A>G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM2 PP3_Moderate PP5_Very_Strong

The NM_000535.7(PMS2):​c.2002A>G​(p.Ile668Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000751098: Studies have shown that this missense change results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID:25691505, 34489406)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I668M) has been classified as Uncertain significance. The gene PMS2 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 7.10
• Publications: 15 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: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000751098: Studies have shown that this missense change results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 25691505, 34489406).; SCV001344501: A functional study using cells from a carrier individual has shown that the cryptic donor site is utilized, and the aberrant splicing product results in a premature protein truncation (PMID: 25691505). However, the study also observed small amounts of full-length transcript were also produced from the mutant allele, indicating the leakiness of the cryptic donor site. These full-length transcripts were observed in association with functional partner MLH1 protein. The splicing defect has also been observed in a mouse-model with the mouse equivalent variant, c.1993A>G (PMID: 36715493).; SCV006051986: Functional studies have demonstrated that this variant results in abnormal splicing through use of an alternate donor (Li L et al. J Med Genet, 2015 May;52:348-52).; SCV003853150: Published functional studies demonstrate a damaging effect on splicing resulting in an abnormal transcript that is subject to nonsense mediated decay (Li et al., 2015; Biswas et al., 2021); SCV004187588: Functional studies indicate this variant impacts protein function [PMID: 25691505, 34489406, 30608896].
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-5986763-T-C is Pathogenic according to our data. Variant chr7-5986763-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 192316.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.2002A>G	p.Ile668Val	missense	Exon 11 of 15	NP_000526.2	P54278-1
	PMS2	NM_001406866.1		c.2188A>G	p.Ile730Val	missense	Exon 12 of 16	NP_001393795.1	A0A8V8TNX6
	PMS2	NM_001322014.2		c.2002A>G	p.Ile668Val	missense	Exon 11 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.2002A>G	p.Ile668Val	missense	Exon 11 of 15	ENSP00000265849.7	P54278-1
	PMS2	ENST00000382321.5	TSL:1	c.804-3772A>G		intron	N/A	ENSP00000371758.4	P54278-2
	PMS2	ENST00000406569.8	TSL:1	n.1678+324A>G		intron	N/A	ENSP00000514464.1	P54278-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Hereditary cancer-predisposing syndrome (2)
2	-	-	not provided (2)
1	-	-	Hereditary nonpolyposis colorectal neoplasms (1)
1	-	-	Lynch syndrome 4 (1)
1	-	-	Lynch syndrome 4;C5436817:Mismatch repair cancer syndrome 4 (1)
1	-	-	Mismatch repair cancer syndrome 4 (1)
-	-	-	Lynch syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.1
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.13
Sift	Benign	0.19	T
Sift4G	Benign	0.066	T
Polyphen		0.57	P
Vest4		0.65
MutPred		0.27		Gain of catalytic residue at I668 (P = 0.0942)
MVP		0.57
MPC		2.9
ClinPred		0.95	D
GERP RS		5.8
Varity_R		0.16
gMVP		0.32
Mutation Taster		=25/75	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.97		Position offset: 1
DS_DL_spliceai		0.49		Position offset: -4

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

Other links and lift over

dbSNP: rs869320619; hg19: chr7-6026394;