Submissions for variant NM_000535.7(PMS2):c.137G>A (p.Ser46Asn) (rs121434629)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000076806	SCV000592922	likely pathogenic	Lynch syndrome	2014-12-11	criteria provided, single submitter	clinical testing
Invitae	RCV000524431	SCV000552059	likely pathogenic	Hereditary nonpolyposis colon cancer	2018-11-16	criteria provided, single submitter	clinical testing	This sequence change replaces serine with asparagine at codon 46 of the PMS2 protein (p.Ser46Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. This variant is present in population databases (rs121434629, ExAC 0.003%). This variant has been reported in individuals with a personal or family history of colorectal cancer and sebaceous adenoma (PMID: 26866578, 25006859). This variant has also been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with constitutional mismatch repair deficiency syndrome (PMID: 18273873). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 91301). Experimental studies have shown that this missense change disrupts PMS2 mismatch repair activity (PMID: 24027009). A different missense substitution at this codon (p.Ser46Ile) has been determined to be pathogenic (PMID: 22577899, 23709753). This suggests that the serine residue is critical for PMS2 protein function and that other missense substitutions at this position may also be pathogenic. 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.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic	RCV000584471	SCV000691980	pathogenic	not provided		no assertion criteria provided	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000584471	SCV000888391	likely pathogenic	not provided	2018-07-12	criteria provided, single submitter	clinical testing

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