7-5987209-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.1556A>G(p.Tyr519Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000607 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. Y519H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:9
• Conservation: PhyloP100: -2.84

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=0.010536045).
• BP6: Variant 7-5987209-T-C is Benign according to our data. Variant chr7-5987209-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135939.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=7, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.1556A>G	p.Tyr519Cys	missense_variant	11/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.1556A>G	p.Tyr519Cys	missense_variant	11/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000836 AC: 21 AN: 251300 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135858

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000534 AC: 78 AN: 1461788 Hom.: 0 Cov.: 45 AF XY: 0.0000578 AC XY: 42 AN XY: 727190

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74448

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000843 Hom.: 0

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 23, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PMS2 p.Tyr519Cys variant was identified in 10 of 2298 proband chromosomes (frequency: 0.004) from individuals or families with breast cancer or lynch syndrome (Balogh 2006, Lagerstedt-Robinson 2016, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs63750649) as “With Uncertain significance allele", ClinVar (classified as likely benign by Invitae and Ambry Genetics; as uncertain significance by Counsyl, GeneDx and Fulgent Genetics), Clinvitae, MutDB, Mismatch Repair Genes Variant Database, and in Insight Hereditary Tumors Database (3x, effect unknown). The variant was not identified in COGR, Cosmic, or Zhejiang University databases. The variant was identified in control databases in 24 of 277074 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 2 of 6464 chromosomes (freq: 0.0003), Latino in 11 of 34416 chromosomes (freq: 0.0003), European in 7 of 126622 chromosomes (freq: 0.0001), and South Asian in 4 of 30780 chromosomes (freq: 0.0001); it was not observed in the African, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Tyr519 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. A functional in vitro study by Drost (2013) identified MMR activity of the variant in comparison to a negative control suggesting a neutral effect of the variant on protein function. In addition two patients identified with the c.1556A>G variant were also found to have a co-occurring pathogenic variant: MSH2, c.2210+1G>A and PMS2, c.1492del11, suggesting that the c.1556A>G variant may not be of clinical significance (Yurgelun 2015, Nomura 2015). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	PMS2: PS3:Supporting, BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 16, 2017	This variant is denoted PMS2 c.1556A>G at the cDNA level, p.Tyr519Cys (Y519C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). PMS2 Tyr519Cys has been reported in at least two individuals with suspected Lynch syndrome, one of whom was also found to harbor a pathogenic MSH2 variant (Yurgelun 2015, Lagerstedt-Robinson 2016). It was also identified in an individual with an MSI-high, PMS2-deficient rectal cancer and a truncating PMS2 variant (Nomura 2015). However, the methodology used by Nomura et al. would not be able to distinguish whether Tyr519Cys was identified in PMS2 or its pseudogene, PMS2CL. This variant demonstrated efficient mismatch repair activity in comparison to a repair-deficient control in an in vitro functional assay (Drost 2013). Although this variant was observed in 1000 Genomes, population data in this region of PMS2 are not considered reliable due to high pseudogene homology. Since Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Tyr519Cys occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether PMS2 Tyr519Cys is pathogenic or benign. We consider it to be a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 26, 2022	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 14, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 15, 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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 06, 2021	- -

Lynch syndrome 4 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 04, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 08, 2024	Variant summary: PMS2 c.1556A>G (p.Tyr519Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.1e-05 in 1614072 control chromosomes, predominantly at a frequency of 0.00042 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 3.7 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 a benign polymorphism found primarily in populations of Latino origin. c.1556A>G has been reported in the literature in individuals affected with Lynch syndrome-associated cancers or with suspected Lynch Syndrome (e.g., Yurgelun_2015, Nomura_2015, Lagerstedt-Robinson_2016, Balogh_2006, Okkels_2019, Li_2020), frequently along with PMS2 c.1559C>T (p.A520V; Yurgelun_2015, Nomura_2015, Okkels_2019). However, the variant was found not to segregate with disease in at least one family (e.g., Okkels_2019) and was also classified as a benign/likely benign polymorphism in several publications (e.g., Okkels_2019, Li_2020, Balogh_2006). These reports are not suggestive that the variant is associated with Lynch Syndrome. Additionally, co-occurrences with other pathogenic variants have been reported (MSH2 c.2210+1G>A (Yurgelun_2015); PMS2 c.1492_1502del11 (p.Ser498GlyfsX3; Nomura_2015); MLH1 c.677+3A>G (Okkels_2019); MLH1 c.(1731+1_1732-1)_(*194_?)del, E16-19del (Okkels_2019)), providing supporting evidence for a benign role. Several publications report experimental evidence evaluating an impact on protein function, suggesting the variant does not greatly disrupt normal protein function (e.g., Drost_2013, Nomura_2015, Okkels_2019). The following publications have been ascertained in the context of this evaluation (PMID: 22290698, 17016615, 24027009, 27601186, 31391288, 26232782, 31433215, 25980754). ClinVar contains an entry for this variant (Variation ID: 135939). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Lynch syndrome 4;C5399763:Mismatch repair cancer syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2017

- -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

May 11, 2021

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	0.012
Dann	Benign	0.30
DEOGEN2	Benign	0.052	T;.;.;.;.
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.0032	N
LIST_S2	Benign	0.14	T;T;.;T;.
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.011	T;T;T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	-0.77	N;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	1.1	N;N;.;.;.
REVEL	Benign	0.19
Sift	Benign	0.18	T;T;.;.;.
Sift4G	Benign	0.18	T;T;.;.;.
Polyphen		0.0	B;B;.;.;B
Vest4		0.57
MutPred		0.17		Loss of phosphorylation at Y519 (P = 0.0068);.;.;.;.;
MVP		0.23
MPC		0.042
ClinPred		0.042	T
GERP RS		-12
Varity_R		0.027
gMVP		0.18

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: rs63750649; hg19: chr7-6026840; COSMIC: COSV105851240;