Submissions for variant NM_000535.7(PMS2):c.2108C>T (p.Thr703Met)

gnomAD frequency: 0.00016  dbSNP: rs370196722

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000587414	SCV000149582	uncertain significance	not provided	2022-07-11	criteria provided, single submitter	clinical testing	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)
Ambry Genetics	RCV000115673	SCV000184278	likely benign	Hereditary cancer-predisposing syndrome	2021-10-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV000456314	SCV000551952	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000855604	SCV000697327	likely benign	not specified	2023-03-07	criteria provided, single submitter	clinical testing	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.
Counsyl	RCV000662645	SCV000785332	uncertain significance	Lynch syndrome 4	2017-07-07	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000115673	SCV000822129	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587414	SCV000889620	uncertain significance	not provided	2020-10-13	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000855604	SCV002069247	uncertain significance	not specified	2021-12-22	criteria provided, single submitter	clinical testing	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.
Sema4, Sema4	RCV000115673	SCV002530259	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-14	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002505034	SCV002814788	uncertain significance	Lynch syndrome 4; Mismatch repair cancer syndrome 4	2022-04-16	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662645	SCV004019884	uncertain significance	Lynch syndrome 4	2023-04-05	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV000662645	SCV004205370	uncertain significance	Lynch syndrome 4	2023-10-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115673	SCV004359553	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-23	criteria provided, single submitter	clinical testing	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.