7-5992008-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000535.7(PMS2):c.953A>G(p.Tyr318Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000221 in 1,600,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. Y318H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:14
• Conservation: PhyloP100: 7.67

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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04951796).
• BP6: Variant 7-5992008-T-C is Benign according to our data. Variant chr7-5992008-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41722.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Likely_benign=7, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.953A>G	p.Tyr318Cys	missense_variant	9/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.953A>G	p.Tyr318Cys	missense_variant	9/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152156 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000434 AC: 109 AN: 251296 Hom.: 0 AF XY: 0.000449 AC XY: 61 AN XY: 135852

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00694

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000967

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.000223 AC: 323 AN: 1448592 Hom.: 0 Cov.: 27 AF XY: 0.000270 AC XY: 195 AN XY: 721538

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00714

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000349

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000473

Gnomad4 OTH exome AF: 0.000700

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152274 Hom.: 0 Cov.: 31 AF XY: 0.000201 AC XY: 15 AN XY: 74442

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000399 Hom.: 0

Bravo AF: 0.000196

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000354 AC: 43

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:14

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 14, 2021	This variant is associated with the following publications: (PMID: 22703879, 25801821, 25151201, 26689913, 27498913, 27739435, 25479140, 22949387, 23376243) -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 23, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 31, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	PMS2: BP1 -

Hereditary cancer-predisposing syndrome Benign:5

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Aug 10, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 13, 2018	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. -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Dec 01, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 09, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Sep 26, 2023	- -

not specified Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 27, 2020	Variant summary: PMS2 c.953A>G (p.Tyr318Cys) results in a non-conservative amino acid change located in the DNA mismatch repair protein, C-terminal (IPR013507) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00051 in 254040 control chromosomes. Although pseudogene interference cannot be completely ruled out, this allele frequency is likely accurate because there are several mismatches between PMS2 and the pseudogene within 25 bases upstream of the variant of interest, increasing the likelihood of specificity. The observed variant frequency is approximately 4.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Lynch Syndrome phenotype (0.00011), strongly suggesting that the variant is benign. c.953A>G has been reported in the literature in sequencing studies of individuals affected with prostrate cancer, healthy AJ centenarians with no evidence of cancer, and BRCA testing cohorts (example, Grant_2015, Han_2013, Tung_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. At-least two co-occurrences with other pathogenic variants have been reported (BRCA1 c.68_69del, p.Glu23ValfsX17)(Tung_2015) and MSH6 c.3984_3987dupGTCA, p.Leu1330fsX12 at our laboratory), providing additional supporting evidence for a benign role. Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign (1)/likely benign(7), n=8 and VUS, n=3). Based on the evidence outlined above, the variant was re-classified from likely benign to benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 31, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is classified as DP in HGMD. It has been seen in one 4 control alleles and 10 centenarian alleles in one study. It is classified in ClinVar with 2 stars as Likely benign/benign by 4 submitters (Invitae, Ambry, GeneDx, Biesecker lab). MaxMAF = 0.05% in ExAC (high for disease incidence). -

Lynch syndrome 4 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PMS2 p.Tyr318Cys variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was also identified in dbSNP (ID: rs139438201) as With other allele, ClinVar (classified as benign by Invitae; classified as likely benign by GeneDx, Ambry Genetics; classified as uncertain significance by LMMPHPM), databases. The variant was not identified in Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database, databases. The variant was identified in control databases in 108 of 277068 chromosomes at a frequency of 0.00039 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Tyr318 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the DNA mismatch repair protein, C-terminal DNA mismatch repair protein family Ribosomal protein S5 domain 2-type fold functional domains increasing the likelihood that it may have clinical significance. In addition, the variant was found in Allelotypic analysis of novel nsSNPs and was found in 4 (1 homozygous) of 410 AJ controls and in 10 of 390 centenarians. The p.Y318C variant showed significant enrichment (5.3 fold, p=0.02) in PMS2 (Han 2013). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

PMS2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 09, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;.;.;.;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;.;D;.
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.050	T;T;T;T;T
MetaSVM	Uncertain	0.70	D
MutationAssessor	Pathogenic	3.4	M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-7.1	D;D;.;.;.
REVEL	Pathogenic	0.83
Sift	Uncertain	0.024	D;D;.;.;.
Sift4G	Uncertain	0.060	T;T;.;.;.
Polyphen		1.0	D;D;.;.;D
Vest4		0.94
MVP		0.92
MPC		0.29
ClinPred		0.21	T
GERP RS		5.4
Varity_R		0.83
gMVP		0.63

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: rs139438201; hg19: chr7-6031639;