ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2444C>T (p.Ser815Leu) (rs587779338)

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Total submissions: 6
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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 2020-08-18 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 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 2018-07-31 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.2444C>T at the cDNA level, p.Ser815Leu (S815L) at the protein level, and results in the change of a Serine to a Leucine (TCG>TTG). This variant has been reported in the heterozygous state in several patients with Lynch syndrome, with tumors from two such individuals showing absent PMS2 expression on immunohistochemistry (van der Klift 2010, Brea-Fernandez 2014, ten Broeke 2015, van der Klift 2016). PMS2 Ser815Leu has also been observed in the homozygous state in an individual with constitutional mismatch repair deficiency (Suerink 2017). In vitro functional studies have found that PMS2 Ser815Leu results in deficient mismatch repair activity similar to a known pathogenic missense variant, PMS2 Ser46Ile (van der Klift 2016, Gonzalez-Acosta 2017). PMS2 Ser815Leu was not observed in large population cohorts (Lek 2016). This variant is located within the endonuclease domain (Fukui 2011). In silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on the currently available evidence, we consider PMS2 Ser815Leu to be a likely pathogenic variant.
Invitae RCV000525929 SCV000625619 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-11-24 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 815 of the PMS2 protein (p.Ser815Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. The frequency data for this variant in the population databases (rs587779338, ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has been observed in several individuals affected with colorectal cancer or other Lynch syndrome-related tumors (PMID: 23837913, 27435373, 20186688, 26110232, 25512458), and in two individuals with features consistent with constitutional mismatch repair deficiency (CMMRD) (PMID: 28503822, Invitae). This variant was also reported to segregate in a Lynch syndrome family (PMID: 28365877). ClinVar contains an entry for this variant (Variation ID: 91343). Experimental studies have shown that this missense change causes a significant reduction in PMS2 mismatch repair activity in vitro (PMID: 27435373, 28365877). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000764719 SCV000895854 uncertain significance Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 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 2019-05-03 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, dimerization domain (IPR014790) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 5/5 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_PMS2_CG_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. Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (4x likely pathogenic and 1x uncertain significance). Based on the evidence outlined above, the variant was classified as pathogenic.

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