chr7-6004002-C-T

Variant names:

• chr7-6004002-C-T
• rs1554304979
• NM_000535.7:c.220G>A

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP3_Strong PP5

The NM_000535.7(PMS2):​c.220G>A​(p.Gly74Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G74E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 5.75
• 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: Pathogenic. The variant received 19 ACMG points.

• PS1: Transcript NM_000535.7 (PMS2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 45 uncertain in NM_000535.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-6004001-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2674188.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 7-6004002-C-T is Pathogenic according to our data. Variant chr7-6004002-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 455692.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7	c.220G>A	p.Gly74Arg	missense_variant	Exon 3 of 15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.220G>A	p.Gly74Arg	missense_variant	Exon 3 of 15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Nov 13, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G74R variant (also known as c.220G>A), located in coding exon 3 of the PMS2 gene, results from a G to A substitution at nucleotide position 220. The glycine at codon 74 is replaced by arginine, an amino acid with dissimilar properties. This alteration was identified in an individual diagnosed with early-onset colorectal cancer whose family history met Amsterdam I criteria for Lynch syndrome (Ambry internal data). Another alteration with a different nucleotide change but the same amino acid change, c.220G>C (p.G74R), has been reported as likely pathogenic due to it being identified in individuals whose colorectal tumors displayed high microsatellite instability (MSI-H) with either absent or weak PMS2 staining on immunohistochemistry (IHC) and an internal structural assessment determined p.G74R causes significant structural destabilization of the ATPase domain (Ambry internal data). 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 Uncertain:1

May 01, 2018

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PMS2 NM_000535.5:c.220G>A has a 60.9% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the PMS2 locus. See Shirts et al 2018, PMID 29887214. -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Dec 20, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 74 of the PMS2 protein (p.Gly74Arg). This variant is not present in population databases (gnomAD no frequency). 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. 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. ClinVar contains an entry for this variant (Variation ID: 455692). This missense change has been observed in individual(s) with clinical features of PMS2-related conditions (Invitae). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D;D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	4.8	H;H
PhyloP100		5.8
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-7.1	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.95
MutPred		0.95		Loss of catalytic residue at N71 (P = 0.1144);Loss of catalytic residue at N71 (P = 0.1144);
MVP		0.97
MPC		0.29
ClinPred		1.0	D
GERP RS		5.7
PromoterAI		-0.015	Neutral
Varity_R		0.99
gMVP		0.91
Mutation Taster		=13/187	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

Other links and lift over

dbSNP: rs1554304979; hg19: chr7-6043633;