Submissions for variant NM_000251.3(MSH2):c.2606C>A (p.Ala869Glu)

gnomAD frequency: 0.00001  dbSNP: rs730881772

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000759828	SCV000211222	uncertain significance	not provided	2021-09-23	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history of renal or colorectal cancer (Yehia 2018, Erdem 2020); This variant is associated with the following publications: (PMID: 29684080, 32283892)
Invitae	RCV000203841	SCV000262339	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-10-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000565478	SCV000664849	likely benign	Hereditary cancer-predisposing syndrome	2022-03-03	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.
Mendelics	RCV000708846	SCV000837858	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759828	SCV000889430	uncertain significance	not provided	2017-09-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000565478	SCV001347192	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-14	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with glutamic acid at codon 869 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 colorectal cancer (PMID: 32283892) and an individual affected with kidney cancer (PMID: 29684080). This variant has been identified in 2/251418 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193897	SCV001363057	uncertain significance	not specified	2022-10-03	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.2606C>A (p.Ala869Glu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251418 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2606C>A has been reported in the literature as a VUS in settings of multigene panel testing among individuals with features of Cowden/Cowden-like (CS/CS-like) and Bannayan-Riley-Ruvalcaba syndromes (BRRS) without strong evidence for causality (Yehia_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003467250	SCV004194547	uncertain significance	Lynch syndrome 1	2023-06-14	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000708846	SCV004826553	uncertain significance	Lynch syndrome	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with glutamic acid at codon 869 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 colorectal cancer (PMID: 32283892) and an individual affected with kidney cancer (PMID: 29684080). This variant has been identified in 2/251418 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	RCV001354344	SCV001548939	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH2 p.Ala869Glu variant was not identified in the literature nor was it identified in the following databases: GeneInsight-COGR, Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs730881772) as “With Uncertain significance allele”, ClinVar (as uncertain significanceby GeneDx, Invitae, and Ambry Genetics), Clinvitae, and UMD-LSDB (1x as uncertain significance). The variant was identified in control databases in 2 of 246212 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (Non-Finnish) in 2 of 111684 chromosomes (freq: 0.000018), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Ala869 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000759828	SCV002035421	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000759828	SCV002038263	uncertain significance	not provided		no assertion criteria provided	clinical testing