Submissions for variant NM_000251.3(MSH2):c.1182T>G (p.Phe394Leu)

gnomAD frequency: 0.00002  dbSNP: rs374135434

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212598	SCV000149405	uncertain significance	not provided	2023-01-23	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with breast cancer (Jalkh et al., 2017); This variant is associated with the following publications: (PMID: 28202063, 18822302, 21120944)
Ambry Genetics	RCV000115496	SCV000184289	likely benign	Hereditary cancer-predisposing syndrome	2023-05-16	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.
Invitae	RCV000477595	SCV000548230	benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115496	SCV000684913	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 394 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with breast cancer (PMID: 28202063). This variant has been identified in 5/282800 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.
Counsyl	RCV000663103	SCV000786218	uncertain significance	Lynch syndrome 1	2018-03-23	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000212598	SCV000884131	uncertain significance	not provided	2017-11-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212598	SCV001134330	uncertain significance	not provided	2019-04-19	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818271	SCV002066714	uncertain significance	not specified	2020-12-02	criteria provided, single submitter	clinical testing	DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.1182T>G, in exon 7 that results in an amino acid change, p.Phe394Leu. This sequence has been described in the gnomAD database in five individuals with an overall population frequency of 0.0018% (dbSNP rs374135434), and has also been reported in one individual with breast cancer (PMID: 28202063). The p.Phe394Leu change affects a highly conserved amino acid residue located in a domain of the MSH2 protein that is known to be functional. The p.Phe394Leu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Phe394Leu change remains unknown at this time.
Myriad Genetics, Inc.	RCV000663103	SCV004018339	likely benign	Lynch syndrome 1	2023-10-03	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726].
Baylor Genetics	RCV000663103	SCV004194504	uncertain significance	Lynch syndrome 1	2023-07-24	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997267	SCV004832535	uncertain significance	Lynch syndrome	2024-01-08	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 394 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with breast cancer (PMID: 28202063). This variant has been identified in 5/282800 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.