Submissions for variant NM_000251.3(MSH2):c.1804C>G (p.Leu602Val)

gnomAD frequency: 0.00001  dbSNP: rs748797209

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000205416	SCV000259674	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000221565	SCV000275993	likely benign	Hereditary cancer-predisposing syndrome	2022-02-14	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.
GeneDx	RCV000235312	SCV000293865	uncertain significance	not provided	2023-05-11	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history including colorectal cancer and acute lymphoblastic leukemia (Zhang et al., 2015; Borras et al., 2017); Published functional studies suggest this variant is more likely to be deleterious (Jia et al., 2020); This variant is associated with the following publications: (PMID: 26580448, 28765196, 33357406, 9774676, 18822302, 21120944)
Color Diagnostics, LLC DBA Color Health	RCV000221565	SCV000684978	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-27	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 602 of the MSH2 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). 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 not been reported in individuals affected with MSH2-associated hereditary cancer in the literature. This variant has been identified in 3/251466 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	RCV000663070	SCV000786137	uncertain significance	Lynch syndrome 1	2018-03-07	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000663070	SCV001299645	uncertain significance	Lynch syndrome 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Myriad Genetics, Inc.	RCV000663070	SCV004018257	likely benign	Lynch syndrome 1	2023-03-17	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: 25085752].
Baylor Genetics	RCV000663070	SCV004196816	uncertain significance	Lynch syndrome 1	2023-06-05	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997576	SCV004827377	uncertain significance	Lynch syndrome	2023-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 602 of the MSH2 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). 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 not been reported in individuals affected with MSH2-associated hereditary cancer in the literature. This variant has been identified in 3/251466 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356036	SCV001551090	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH2 p.Leu602Val variant was not identified in the literature nor was it identified in Cosmic, MutDB, UMD-LSDB, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs748797209 as With Uncertain significance allele) and ClinVar (4x as a variant of uncertain significance). The variant was also identified in control databases in 3 of 246242 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European Non-Finnish population in 3 of 111704 chromosomes (freq: 0.00003) and was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Leu602 residue is conserved in mammals. However, computational analyses (SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not reliably predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.