7-5973429-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1 BP4_Moderate BP6 BS2

The NM_000535.7(PMS2):c.2559C>G(p.Ile853Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. I853V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000043 (0 hom., cov: 11)
  • Exomes 𝑓: 0.000089 (6 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:3 O:1
• Conservation: PhyloP100: -1.19

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain in NM_000535.7
• BP4: Computational evidence support a benign effect (MetaRNN=0.08739734).
• BP6: Variant 7-5973429-G-C is Benign according to our data. Variant chr7-5973429-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 142688.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=9, Benign=1, Likely_benign=2, not_provided=1}.
• BS2: High Homozygotes in GnomAdExome at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.2559C>G	p.Ile853Met	missense_variant	15/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.2559C>G	p.Ile853Met	missense_variant	15/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes AF: 0.0000433 AC: 4 AN: 92284 Hom.: 0 Cov.: 11

Gnomad AFR AF: 0.0000419

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: 0.0000665

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000113 AC: 23 AN: 203794 Hom.: 2 AF XY: 0.000171 AC XY: 19 AN XY: 111020

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000705

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000276

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000157

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000893 AC: 79 AN: 884854 Hom.: 6 Cov.: 12 AF XY: 0.000112 AC XY: 51 AN XY: 455478

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000278

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000295

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000905

Gnomad4 OTH exome AF: 0.0000252

GnomAD4 genome AF: 0.0000433 AC: 4 AN: 92284 Hom.: 0 Cov.: 11 AF XY: 0.00 AC XY: 0 AN XY: 43238

Gnomad4 AFR AF: 0.0000419

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000665

Gnomad4 OTH AF: 0.00

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000247 AC: 2

ExAC AF: 0.000158 AC: 18

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 02, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 02, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	PMS2: PP2, BP4, BS3:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate no damaging effect: similar to wild type in assays assessing RNA and protein expression, viability, apoptosis induction, and DNA damage signaling (Arora et al., 2017); Observed in individuals with a personal or family history including breast, pancreatic, and prostate cancer (Tung et al., 2015; Dudley et al., 2018); This variant is associated with the following publications: (PMID: 29360161, 25186627, Fukui2011[Chapter], 28494185) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 13, 2023	In the published literature, the variant has been reported in individuals with pancreatic cancer (PMIDs: 29360161 (2018), 27449771 (2016)) and breast cancer (PMID: 25186627 (2015)). A cell line-based functional study showed this variant has neutral to mild effect on protein expression, cell viability, and DNA damage response signaling (PMID: 28494185 (2017)). The frequency of this variant in the general population, 0.00028 (7/25322 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Additional analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 31, 2020	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 27, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 28, 2022	This missense variant replaces isoleucine with methionine at codon 853 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has reported the mutant protein to be functional in response to DNA damaging agents and in phosphorylation of downstream target (PMID: 28494185). This variant has been reported in an individual affected with cancer with features suggestive of Lynch syndrome (PMID: 31391288). This variant has been identified in 24/218728 chromosomes in the general population by the Genome Aggregation Database (gnomAD). However, this observed allele frequency is not considered reliable, because the gnomAD dataset does not disambiguate possible interference from homologous sequences in the PMS2CL pseudogene. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 15, 2017	Variant summary: The PMS2 c.2559C>G (p.Ile853Met) variant involves the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 24/214886 control chromosomes at a frequency of 0.0001117, which is approximately equivalent to the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). However, a known PMS2 pseudogene complicates the interpretation of this control population data. The variant has been identified in a pancreatic cancer patient that also carried a CDNK2A mutation (mutation not specified) and a CFTR variant (p.A120T; PoDV), suggesting the variant of interest is not playing a role in cancer development (Yang_2016). In addition, a recent study assessed the functional effects of the variant via in vitro expression assays and cell-based MMR assays, all of which showed no or mild effect on function (Arora_2017). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance without supporting evidence for independent review. Given the functional data and the co-occurrences in a patient, this variant is classified as VUS-possibly benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 06, 2017	The p.Ile853Met variant in PMS2 has not been previously reported in individuals with Lynch syndrome, but has been identified in 7/25524 of South Asian chromosom es by the Genome Aggregation DAtabase (gnomAD http://gnomad.broadinstitute.org; dbSNP rs371673459). Computational prediction tools and conservation analysis sug gest that the p.Ile853Met variant may not impact the protein, though this inform ation is not predictive enough to rule out pathogenicity. In summary, the clinic al significance of the p.Ile853Met variant is uncertain. -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Oct 14, 2021

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Lynch syndrome;C5436817:Mismatch repair cancer syndrome 4 Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant interpreted as Uncertain significance and reported on 07-28-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	0.11
Dann	Benign	0.74
DEOGEN2	Benign	0.13	T;.;.;.;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.88	D;D;.;D;.;D
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.087	T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.1	L;.;.;.;.;.
MutationTaster	Benign	0.92	N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.2	N;N;.;.;.;N
REVEL	Uncertain	0.47
Sift	Benign	0.047	D;T;.;.;.;D
Sift4G	Uncertain	0.035	D;D;.;.;.;D
Polyphen		0.46	P;P;.;.;P;P
Vest4		0.32
MVP		0.47
MPC		2.0
ClinPred		0.075	T
GERP RS		-10
Varity_R		0.073
gMVP		0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs371673459; hg19: chr7-6013060;