7-5973454-T-C

Variant names:

• chr7-5973454-T-C
• rs1554292741
• NM_000535.7:c.2534A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM5 PP3_Moderate PP5

The NM_000535.7(PMS2):​c.2534A>G​(p.His845Arg) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H845Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 10)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 8.01
• Publications: 1 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 54 uncertain in NM_000535.7
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-5973453-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1792761.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92
• PP5: Variant 7-5973454-T-C is Pathogenic according to our data. Variant chr7-5973454-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 662202.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7	c.2534A>G	p.His845Arg	missense_variant	Exon 15 of 15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.2534A>G	p.His845Arg	missense_variant	Exon 15 of 15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes Cov.: 10

GnomAD4 exome Cov.: 10

GnomAD4 genome Cov.: 10

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Apr 30, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.H845R variant (also known as c.2534A>G), located in coding exon 15 of the PMS2 gene, results from an A to G substitution at nucleotide position 2534. The histidine at codon 845 is replaced by arginine, an amino acid with highly similar properties. This variant has been identified in a proband whose Lynch syndrome-associated tumor demonstrated loss of PMS2 expression by immunohistochemistry (Ambry internal data). Based on internal structural analysis, H845R disrupts the zinc-binding site of the endonuclease domain, a region sensitive to disruption (Gueneau E et al. Nat Struct Mol Biol, 2013 Apr;20:461-8). Another alteration at the same codon, p.H845L (c.2534A>T), has been detected in multiple probands whose Lynch-associated tumors demonstrated high microsatellite instability and/or loss of PMS2 expression by immunohistochemistry (Goodenberger ML et al. Genet. Med., 2016 Jan;18:13-9; Yurgelun et al. J Clin Oncol 2017 Apr;35(10):1086-1095; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Lynch syndrome 4 Pathogenic:1

Sep 25, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 35451539]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype Uncertain:1

Dec 28, 2017

Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Mar 08, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 845 of the PMS2 protein (p.His845Arg). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 662202). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMS2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;.;.;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;.;D;.;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.8	H;.;.;.;.;.
PhyloP100		8.0
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-6.8	D;D;.;.;.;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;.;.;.;D
Sift4G	Pathogenic	0.0	D;D;.;.;.;D
Polyphen		1.0	D;D;.;.;D;D
Vest4		0.95
MutPred		0.73		Gain of MoRF binding (P = 0.0205);.;.;.;.;.;
MVP		0.95
MPC		3.6
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.91
gMVP		0.98
Mutation Taster		=16/84	disease causing

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

Other links and lift over

dbSNP: rs1554292741; hg19: chr7-6013085;