Submissions for variant NM_000535.7(PMS2):c.1567T>A (p.Ser523Thr)

gnomAD frequency: 0.00021  dbSNP: rs63751132

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656949	SCV000149570	uncertain significance	not provided	2024-06-04	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28135145, 22290698, 15470502, 24728327, 27930734, 32095738, 31992580, 17016615, 26845104, 26976419, 20186688, 26689913, 26232782, 31159747, 31433215, 31391288, 32547938, 28166811, 12900794, 22949379, 34284872, 35449176, 33471991, 30374176, 37937776)
Ambry Genetics	RCV000115661	SCV000187249	likely benign	Hereditary cancer-predisposing syndrome	2018-11-28	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082540	SCV000254601	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV002279936	SCV000266216	likely benign	Hereditary nonpolyposis colon cancer	2019-01-31	criteria provided, single submitter	clinical testing	This variant is found in population databases at a higher frequency than expected for pathogenic variants in the PMS2 gene (exac.broadinstitute.org, Kobayashi 2017). This variant is not located in a functional domain and its genomic position is not highly conserved. Computational algorithms classify this variant as tolerated. This variant has an entry in the ClinVar database (Variation ID: 127763) and has been classified as likely benign by another laboratory where it has been seen in patients with other genetic causes that explain their cancer history. Familial cosegregation analysis showed a likelihood ratio of 0.85 (Thompson 2003), adding more evidence that the variant is benign. Bayesian analysis integrating all this data gives a 2% probability of pathogenicity (Tavtigian 2018, Tsai 2018), which is consistent with a classification of likely benign. Therefore, PMS2 p.S523T is now classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656949	SCV000601824	likely benign	not provided	2022-10-07	criteria provided, single submitter	clinical testing
Counsyl	RCV000662627	SCV000785296	uncertain significance	Lynch syndrome 4	2017-06-29	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000115661	SCV000822123	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115661	SCV000910645	likely benign	Hereditary cancer-predisposing syndrome	2015-04-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121851	SCV000918047	likely benign	not specified	2023-12-18	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1567T>A (p.Ser523Thr) results in a conservative amino acid change located in the outside of any known functional domain or repeat of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251178 control chromosomes, predominantly at a frequency of 0.00046 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (7.1e-05), however this data must be interpreted with caution as the sequencing techology utalized does not distinguish between PMS2 and highly homologous pseudogenes. c.1567T>A has been reported in the literature in individuals affected with Lynch Syndrome and other types of cancer (Nomura_2015, He_2016, Shirts_2016, Tung_2016, Yurgelun_2017, Lu_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (PMS2 c.1492del11; Nomura_2015), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22290698, 26689913, 26845104, 26976419, 27930734, 28135145, 26232782). Fourteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=7) and likely benign (n=7) Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000656949	SCV001502551	likely benign	not provided	2024-05-01	criteria provided, single submitter	clinical testing	PMS2: BP1, BP4, BP5
Sema4, Sema4	RCV000115661	SCV002530204	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-05	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121851	SCV002550711	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149798	SCV003837731	uncertain significance	Breast and/or ovarian cancer	2021-08-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662627	SCV004019882	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.
ITMI	RCV000121851	SCV000086052	not provided	not specified	2013-09-19	no assertion provided	reference population
PreventionGenetics, part of Exact Sciences	RCV003389689	SCV000806144	uncertain significance	PMS2-related disorder	2024-05-20	no assertion criteria provided	clinical testing	The PMS2 c.1567T>A variant is predicted to result in the amino acid substitution p.Ser523Thr. This variant has been reported in individuals with breast cancer and colon cancer (Table 4, Balogh et al. 2006. PubMed ID: 17016615; Table S1, Shirts et al. 2016. PubMed ID: 26845104; Table A2, Tung et al. 2016. PubMed ID: 26976419; Table A4, Yurgelun et al. 2017. PubMed ID: 28135145; Table S5, Tsaousis et al. 2019. PubMed ID: 31159747; Table 1, Okkels et al. 2019. PubMed ID: 31433215; Table 1, Wang et al. 2020. PubMed ID: 31992580). In silico tools predict this variant to be tolerated (Table 3, Ali et al. 2012. PubMed ID: 22290698). This variant is reported in 0.045% of alleles in individuals of South Asian descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127763/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357983	SCV001553600	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The PMS2 p.Ser523Thr variant was identified in 2 of 3900 proband chromosomes (frequency: 0.0005) from individuals or families with breast or colon cancer (Shirts 2015, Tung 2016). The variant was also identified in dbSNP (ID: rs63751132 as "With Uncertain significance allele"), ClinVar (2x as likely benign by Ambry Genetics and Invitae and 4x as uncertain significance by Counsyl, GeneDx, and two other clinical laboratories), Mismatch Repair Genes Variant Database, and InSiGHT Hereditary Tumors database. The variant was not identified in the COGR, Cosmic, MutDB, or Zhejiang University database. The variant was identified in control databases in 46 of 276928 chromosomes at a frequency of 0.0002, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 28 of 126528 chromosomes (freq: 0.0002), Other in 1 of 6464 chromosomes (freq: 0.0002), Latino in 1 of 34418 chromosomes (freq: 0.00003), Finnish in 2 of 25786 chromosomes (freq: 0.00008), and South Asian in 14 of 30782 chromosomes (freq: 0.0005); it was not observed in the African, Ashkenazi Jewish, or East Asian populations. The variant was identified by our lab in an individual with an MLH1/PMS2 deficient rectal tumour with a co-occurring pathogenic MLH1 variant (c.1790G>A, p.Trp597*), increasing the likelihood that the p.Ser523Thr variant does not have clinical significance. The variant was identified with a co-occurring pathogenic PMS2 (PMS2 c.1492del11; Nomura 2015), also increasing the likelihood that the p.Ser523Thr variant does not have clinical significance. The p.Ser523 residue is not conserved in mammals and 3 of 4 computational analyses (PolyPhen-2, SIFT, AlignGVGD, 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 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.