rs63751300

chr7-5987206-G-Achr7-5987206-G-Cchr7-5987206-G-T

Variant summary

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

The NM_000535.7(PMS2):c.1559C>T(p.Ala520Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,613,986 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. A520T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:8
• Conservation: PhyloP100: 0.0520

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=0.014580965).
• BP6: Variant 7-5987206-G-A is Benign according to our data. Variant chr7-5987206-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 185185.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Uncertain_significance=8}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.1559C>T	p.Ala520Val	missense_variant	11/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.1559C>T	p.Ala520Val	missense_variant	11/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152094 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000716 AC: 18 AN: 251252 Hom.: 0 AF XY: 0.0000810 AC XY: 11 AN XY: 135848

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000289

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: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000397 AC: 58 AN: 1461774 Hom.: 0 Cov.: 42 AF XY: 0.0000399 AC XY: 29 AN XY: 727180

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: 0.000104

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74404

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: 0.0000944

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000843 Hom.: 0

ExAC AF: 0.0000741 AC: 9

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

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, 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	GeneDx	Oct 07, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with suspected Lynch syndrome (Yurgelun 2015, Lagerstedt-Robinson 2016, Okkels 2019); This variant is associated with the following publications: (PMID: 31433215, 27601186, 26232782, 20186688, 24362816, 17016615, 25980754, 22290698) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 26, 2022	The frequency of this variant in the general population, 0.00028 (10/35434 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in affected individuals with suspected Lynch syndrome (PMID: 27601186 (2016)), however, the variant was noted to co-occur with a clearly pathogenic variant in a mismatch repair gene (PMIDs: 31433215 (2019), 26232782 (2015), and 25980754 (2015)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 11, 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, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 17, 2016	- -
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.1559C>T (p.Ala520Val) 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 4.7e-05 in 1613986 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 v4.0.0 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.1559C>T 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.1556A>G (p.Y519C; 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. At least one publication reports experimental evidence evaluating an impact on protein function, suggesting the variant does not disrupt protein function, however no data was shown (e.g., Okkels_2019). The following publications have been ascertained in the context of this evaluation (PMID: 22290698, 17016615, 27601186, 31391288, 26232782, 31433215, 25980754). ClinVar contains an entry for this variant (Variation ID: 185185). 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 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense variant c.1559C>T (p.Ala520Val) in PMS2 gene has been reported in the literature in several affected individuals (Yurgelun et.al.,2015). This variant has been reported to the ClinVar database as Uncertain Significance. The p.Ala520Val variant is reported with allele frequency of 0.007076% in gnomAD exomes and novel in gnomAD Exomes and 1000 Genomes. The amino acid Ala at position 520 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ala520Val in PMS2 is predicted as conserved by PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance -

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

- -

Lynch syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jan 08, 2024

- -

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	0.073
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	1.9
Dann	Benign	0.87
DEOGEN2	Benign	0.099	T;.;.;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.40	T;T;.;T;.
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.015	T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.90	L;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.1	N;N;.;.;.
REVEL	Benign	0.090
Sift	Benign	0.27	T;T;.;.;.
Sift4G	Benign	0.29	T;T;.;.;.
Polyphen		0.0020	B;B;.;.;B
Vest4		0.064
MVP		0.21
MPC		0.036
ClinPred		0.022	T
GERP RS		-2.8
Varity_R		0.016
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs63751300; hg19: chr7-6026837; COSMIC: COSV56220880;