rs370196722

Positions:

• chr7-5982890-G-A
• chr7-5982890-G-C
• chr7-5982890-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4 BP6

The NM_000535.7(PMS2):​c.2108C>T​(p.Thr703Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000449 in 1,603,202 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. T703K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:3
• Conservation: PhyloP100: 10.0

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 Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 uncertain in NM_000535.7
• BP4: Computational evidence support a benign effect (MetaRNN=0.34822008).
• BP6: Variant 7-5982890-G-A is Benign according to our data. Variant chr7-5982890-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127773.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=10, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.2108C>T	p.Thr703Met	missense_variant	12/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.2108C>T	p.Thr703Met	missense_variant	12/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes AF: 0.000139 AC: 21 AN: 151544 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000487

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000582 AC: 13 AN: 223266 Hom.: 0 AF XY: 0.0000411 AC XY: 5 AN XY: 121552

Gnomad AFR exome AF: 0.000863

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000102

Gnomad OTH exome AF: 0.000177

GnomAD4 exome AF: 0.0000351 AC: 51 AN: 1451658 Hom.: 0 Cov.: 30 AF XY: 0.0000388 AC XY: 28 AN XY: 721822

Gnomad4 AFR exome AF: 0.000787

Gnomad4 AMR exome AF: 0.0000229

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000199

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome AF: 0.000139 AC: 21 AN: 151544 Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 10 AN XY: 74004

Gnomad4 AFR AF: 0.000487

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: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000147

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000661 AC: 8

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 14, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 23, 2022	This missense variant replaces threonine with methionine at codon 703 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected of having Lynch syndrome (PMID: 25980754). This variant has been identified in 19/254432 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 18, 2021	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. -

Lynch syndrome 4 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jul 07, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 17, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 05, 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 provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 11, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in a patient with a personal history of a Lynch syndrome-associated cancer and/or polyps (Yurgelun 2015); This variant is associated with the following publications: (PMID: 18619468, Fukui2011[Chapter], 25980754, 31159747) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 13, 2020	- -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 07, 2023	Variant summary: PMS2 c.2108C>T (p.Thr703Met) results in a non-conservative amino acid change located in the C-terminal dimerisation domain (IPR014790) 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 5.8e-05 in 223266 control chromosomes, predominantly at a frequency of 0.00086 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 12-fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (7.1e-05), suggesting that the variant is a benign polymorphism. Although the technology utilized for this dataset does not rule out pseudogene interference and thus might not allow unequivocal conclusions about variant significance. c.2108C>T has been reported in the literature in one individual being tested for Lynch Syndrome (Yurgelun_2015) as well as in one individual who had genetic testing for hereditary cancer and personal of family history of breast and/or ovarian cancer (Tsaousis_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrences with other pathogenic variants have been reported (PALB2 c.509_510delGA (p.Arg170IlefsX14); APC c.4054_4063delGTTGAATTTT (p.Val1352LeufsX60); MSH2 c.1226_1227delAG (p.Gln409ArgfsX7); in internal LCA samples), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, mostly without evidence for independent evaluation, and classified the variant as VUS (n=8), or likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 22, 2021	This sequence change has been previously described in an individual with history of LS-associated cancer and/or colorectal polyps(PMID: 25980754). This sequence change has been described in the gnomAD database with a frequency of 0.080% in the African subpopulation (dbSNP rs370196722); however, population data in this region of PMS2 is not considered reliable due to high pseudogene homology. The p.Thr703Met change affects a moderately conserved amino acid residue located in a domain of the PMS2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Thr703Met substitution. Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Thr703Met change remains unknown at this time. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 16, 2022

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.24	T;.;.;.;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;.;D;.;D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.35	T;T;T;T;T;T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.5	M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.6	D;D;.;.;.;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0060	D;D;.;.;.;D
Sift4G	Uncertain	0.0020	D;D;.;.;.;D
Polyphen		1.0	D;D;.;.;D;D
Vest4		0.68
MVP		0.88
MPC		3.3
ClinPred		0.46	T
GERP RS		4.7
Varity_R		0.57
gMVP		0.65

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: rs370196722; hg19: chr7-6022521;