Submissions for variant NM_000251.3(MSH2):c.2558A>C (p.Glu853Ala)

gnomAD frequency: 0.00003  dbSNP: rs63750797

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164439	SCV000215079	likely benign	Hereditary cancer-predisposing syndrome	2022-10-21	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	RCV000656884	SCV000565205	uncertain significance	not provided	2023-08-15	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; Published functional studies suggest a neutral effect: restored mismatch repair (MMR) function in a MSH2 knockout cell line (Jia et al., 2020); Not observed in any cases, but was observed in unaffected controls from a colorectal cancer/polyposis study (Rosenthal et al., 2018); Observed in individuals with suspected Lynch syndrome; however, the variant did not co-segregate with the disease in the family (Kurzawski et al., 2002); This variant is associated with the following publications: (PMID: 26333163, 16451135, 18383312, 11879922, 18822302, 21120944, 33357406, 12362047, 30267214)
Invitae	RCV000541354	SCV000625388	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164439	SCV000685056	likely benign	Hereditary cancer-predisposing syndrome	2023-03-06	criteria provided, single submitter	clinical testing
Counsyl	RCV000663223	SCV000786416	uncertain significance	Lynch syndrome 1	2018-05-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000656884	SCV000806032	uncertain significance	not provided	2018-01-02	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000164439	SCV002534488	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-09	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000663223	SCV004018380	benign	Lynch syndrome 1	2023-11-06	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease. 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].
All of Us Research Program, National Institutes of Health	RCV003997165	SCV004826464	likely benign	Lynch syndrome	2023-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with alanine at codon 853 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in a family affected with hereditary non-polyposis colorectal cancer, who also carried a pathogenic variant in the same gene (PMID: 11879922, 12362047, 16451135). It was reported that this variant did not segregate with disease in this family (PMID: 12362047). This variant has been identified in 4/282858 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000484878	SCV000691913	uncertain significance	not specified		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356683	SCV001551922	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH2 p.Glu853Ala variant was identified in 3 of 450 proband chromosomes (frequency: 0.006) from individuals or families with colorectal cancer or Lynch syndrome-associated cancer from Poland (Kurzawski 2002, Kurzawski 2006, Kurzawski 2002). The variant was also identified in dbSNP (ID: rs63750797) as “With Uncertain significance allele”, ClinVar (classified as uncertain significance by InSiGHT, Ambry Genetics, GeneDx, Invitae, Color, Counsyl, Prevention Genetics, and Mayo Clinic). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 5 of 277226 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24040 chromosomes (freq: 0.00004) and European in 4 of 126708 chromosomes (freq: 0.00003); it was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish or South Asian populations. The p.Glu853 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. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.