Submissions for variant NM_000535.7(PMS2):c.2444C>T (p.Ser815Leu)

gnomAD frequency: 0.00002  dbSNP: rs587779338

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076859	SCV000108351	likely pathogenic	Lynch syndrome	2018-10-18	reviewed by expert panel	curation	Abrogated MMR activity in 2 independent labs, 4 MSI-H/IHC loss tumors, MAF<0.01, 1 Ams family with 2 non-proband affected carriers.
Ambry Genetics	RCV000130249	SCV000185093	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-11-13	criteria provided, single submitter	clinical testing	The p.S815L variant (also known as c.2444C>T), located in coding exon 14 of the PMS2 gene, results from a C to T substitution at nucleotide position 2444. The serine at codon 815 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been detected in several individuals with Lynch associated cancers that demonstrated high microsatellite instability (MSI-H) and/or loss of PMS2 on immunohistochemistry (IHC) (van der Klift HM et al. Hum. Mutat. 2010 May;31:578-87; van der Klift HM et al. Hum. Mutat. 2016 Nov;37:1162-1179). It has also been reported in a homozygous state in a child with features of CMMRD and demonstrated severely impaired mismatch activity in an in vitro functional assay (van der Klift HM et al. Hum. Mutat. 2016 Nov;37:1162-1179; Suerink M et al. Clin. Genet. 2018 Jan;93:134-137). This alteration was also identified in three affected individuals of a family that met Amsterdam II criteria, and the colorectal tumor of the proband as well as the ovarian tumor of the mother showed MSI-H with loss of PMS2 on IHC (Brea-Fern&aacute;ndez AJ et al. Clin. Genet. 2014 Jun;85:583-8; Gonzalez-Acosta M et al. Fam. Cancer 2017 Oct;16(4):501-507). Additional in vitro functional assays demonstrated decreased MLH1 and PMS2 protein expression as well as impaired MMR activity for the p.S815L variant (Gonzalez-Acosta M et al. Fam. Cancer 2017 Oct;16(4):501-507). Based on internal structural assessment, this alteration is expected to disrupt the interaction of PMS2 with MLH1 (Ambry internal data; Gueneau E et al. Nat. Struct. Mol. Biol. 2013 Apr;20:461-8). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This amino acid position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV000485694	SCV000565423	likely pathogenic	not provided	2022-11-29	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: deficient mismatch repair activity (van der Klift et al., 2016); Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene and has been shown to segregate with affected individuals in one family (van der Klift et al., 2010; Suerink et al., 2016; ten Broeke et al., 2015; Gonzalez-Acosta et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26110232, 23837913, 25512458, 22675565, 22290698, 20186688, 23709753, 27435373, 23435383, 30013564, 28365877, Lukas2018, 28503822, 21552516, 29922827, 35451539, 35532657)
Invitae	RCV000525929	SCV000625619	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-21	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 815 of the PMS2 protein (p.Ser815Leu). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This missense change has been observed in individuals with Lynch syndrome (PMID: 20186688, 23837913, 25512458, 26110232, 27435373, 28503822; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 91343). An algorithm developed specifically for the PMS2 gene suggests that this missense change is likely to be deleterious (PMID: 22290698). Experimental studies have shown that this missense change affects PMS2 function (PMID: 27435373, 28365877). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000764719	SCV000895854	uncertain significance	Mismatch repair cancer syndrome 1; Lynch syndrome 4	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193971	SCV001363169	pathogenic	Hereditary nonpolyposis colon cancer	2022-05-24	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.2444C>T (p.Ser815Leu) results in a non-conservative amino acid change located in the MutL, 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. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1e-05 in 199430 control chromosomes (gnomAD) and has been reported in the literature in individuals affected with colorectal cancer and other Lynch Syndrome related tumors (Brea-Fernandez_2013 , Gonzalez-Acosta_2017, van der Klift_2016). In one family the variant co-segregated with the disease (Gonzalez-Acosta_2017). The variant has also reported in the homozygous state in an individual with constitutional mismatch repair deficiency (Suerink_2017). Experimental evidence suggest that this variant significantly reduce mismatch repair activity and protein expression in vitro (Gonzalez-Acosta_2017, van der Klift_2016). Taken together, these data indicate that the variant is likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV000076859	SCV002556879	likely pathogenic	Lynch syndrome	2020-02-24	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000485694	SCV004024372	likely pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003452993	SCV004187599	likely pathogenic	Lynch syndrome 4	2023-09-25	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 27435373].
Baylor Genetics	RCV003452993	SCV004205369	likely pathogenic	Lynch syndrome 4	2023-10-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130249	SCV004358984	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-25	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 815 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional assays have reported that this variant protein have significantly reduced mismatch repair activity and protein expression compared to wild type (PMID: 27435373, 28365877). This variant has been reported in multiple individuals and families affected with Lynch syndrome-associated cancers (PMID: 20186688, 23837913, 25512458, 26110232, 27435373, 28365877; https://www.lovd.nl/), and has been observed to segregate with disease in one family (PMID: 28365877). This variant has also been observed in a homozygous carrier affected with constitutional mismatch repair deficiency (PMID: 28503822). This variant has been identified in 2/199430 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000076859	SCV004848114	likely pathogenic	Lynch syndrome	2019-08-06	criteria provided, single submitter	clinical testing	The p.Ser815Leu variant in PMS2 has been reported in the heterozygous state in at least 3 individuals with PMS2-related cancers and segregated with disease in 2 affected members of one family (van der Klift 2010, Brea-Fernández 2014, ten Broeke 2015, van der Klift 2016, González-Acosta 2017). It has also been reported in the homozygous or compound heterozygous state in 2 individuals with features of congenital mismatch repair deficiency (CMMRD) and absence of PMS2 protein by IHC (Suerink 2016 and 2018, University of Washington personal communication). This variant has been identified in 0.008% (1/12702) of African chromosomes in gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies suggest that this variant leads to reduced PMS2 protein levels and deficiencies in mismatch repair (van der Klift 2016, González-Acosta 2017). Computational prediction tools and conservation analyses support that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Finally, this variant was classified as Likely Pathogenic on Oct. 18, 2018 by the ClinGen-approved InSiGHT expert panel (SCV000108351.3). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PM3, PS3_Moderate, PP3, PS4_Supporting.