Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4BP6
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.
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]
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM1
?
PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
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
?
BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (MetaRNN=0.34822008).
BP6
?
BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
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}.
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
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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:1Benign: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