Submissions for variant NM_000251.3(MSH2):c.913G>A (p.Ala305Thr)

gnomAD frequency: 0.00008  dbSNP: rs63751454

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656876	SCV000149456	likely benign	not provided	2021-06-11	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 12419761, 22949379, 25637381, 9311737, 9709044, 18383312, 22102614, 27311873, 26333163, 19267393, 11048711, 18822302, 30998989, 21120944)
Ambry Genetics	RCV000115547	SCV000213040	likely benign	Hereditary cancer-predisposing syndrome	2018-10-18	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	RCV001084038	SCV000254431	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115547	SCV000537524	likely benign	Hereditary cancer-predisposing syndrome	2019-09-19	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656876	SCV000601493	uncertain significance	not provided	2019-07-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193245	SCV001361973	likely benign	not specified	2022-08-15	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.913G>A (p.Ala305Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 249030 control chromosomes, predominantly at a frequency of 0.00012 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (6e-05 vs 0.00057), allowing no conclusion about variant significance. c.913G>A has been reported in the literature in individuals affected with colorectal cancer and/or undergoing panel-based genetic testing for Lynch syndrome/Hereditary Nonpolyposis Colorectal Cancer and in the NHLBI Exome Sequencing Project (ESP) cohort (example, Winjen_1997, Winjen_1998, Amendola_2015, Buchanan_2016, Dudley_2018, Kim_2020, Talbot_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch syndrome/Hereditary Nonpolyposis Colorectal Cancer. Several publications report experimental evidence evaluating an impact on protein function (example, Lutzen_2008, Drost_2011, Bouvet_2019, Jia_2021). The results of these studies showed no damaging effect of this variant in measures of MMR activity, no defect in nuclear localization, mismatch binding, ATP release, MSH6 binding and EXO1 binding. Nine submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. Five submitters classified the variant as likely benign, while four classified it as VUS. Based on the reproducible functional evidence as outlined above, and emerging consensus towards a benign outcome, the variant was classified as likely benign.
Genetic Services Laboratory, University of Chicago	RCV001193245	SCV002071715	uncertain significance	not specified	2020-03-05	criteria provided, single submitter	clinical testing	DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.913G>A, in exon 5 that results in an amino acid change, p.Ala305Thr. This sequence change has been described in the gnomAD database with a low population frequency of 0.005% (dbSNP rs63751454). The p.Ala305Thr change affects a highly conserved amino acid residue located in a domain of the MSH2 protein that is known to be functional. The p.Ala305Thr substitution appears to be possibly damaging using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). The p.Ala305Thr variant has been reported in patients with Lynch syndrome (PMIDs: 9311737, 19267393), however functional studies performed have not provided evidence that the p.Ala305Thr variant leads to aberrant MSH2 expression, cellular localization or binding, or that this variant impacts mismatch repair activity (PMID: 22102614; Arnold et al., 2009). Due to these contrasting evidences, the clinical significance of the p.Ala305Thr change remains unknown at this time.
Sema4, Sema4	RCV000115547	SCV002526756	likely benign	Hereditary cancer-predisposing syndrome	2020-12-08	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492427	SCV004239292	likely benign	Breast and/or ovarian cancer	2023-04-27	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004542749	SCV004785118	likely benign	MSH2-related disorder	2024-01-23	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
CSER _CC_NCGL, University of Washington	RCV000148633	SCV000190348	uncertain significance	Colorectal cancer, non-polyposis	2014-06-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000076748	SCV001549588	uncertain significance	Lynch syndrome		no assertion criteria provided	clinical testing	The MSH2 p.Ala305Thr variant was identified in 1 of 368 proband chromosomes (frequency: 0.003) from Dutch individuals or families with HNPCC Lynch Syndrome and was not identified in 200 control chromosomes from healthy individuals (Wijnen 1997, Wijnen 1998). Lutzen et al (2008) used functional assays to show that the variant protein lacks any defect in mismatch binding, ATP-release, MMR activity, subcellular localization or protein-protein interactions. In an in vitro study looking at unclassified variants for possible splicing aberrations, tumours carrying the variant were found to have normal MMR activity, and lymphoblastoid cell line derived cDNA displayed normal wildtype product (Arnold 2009). An in silico model based on multivariate analysis predicted a MAPP-MMR score of 3.55, with anything >4.55 considered deleterious (Chao 2008); while an Australian study using a multifactorial likelihood model predicted the pathogenicity of the variant to be Class 3, (unclassified) (Thompson 2013). The variant was identified in dbSNP (ID: rs63751454) as “With Uncertain significance allele”, Clinvitae database (classification uncertain significance), “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, InSiGHT Colon Cancer Gene Variant Database- (LOVD) (11xX as Class 3), ClinVar database (classification uncertain significance, reviewed by an expert panel, submitters InSIGHT, GeneDx, Ambry Genetics, Invitae and CSER CC NCGL: University of Washington Medical Center), and UMD (1x with ”unclassified variant” classification). This variant was also identified in the NHLBI GO Exome Sequencing Project in 1 of 8600 European American alleles (frequency: 0.0001), and in the Exome Aggregation Consortium database (August 8, 2016) in 6 of 121170 chromosomes (frequency: 0.00005) in the following populations: African in 1 of 10280 chromosomes (frequency: 0.0001) and European (Non-Finnish) in 5 of 66656 chromosomes (frequency: 0.00008), but was not seen in East Asian, European (Finnish), Latino, Other, or South Asian populations. The p.Ala305 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. 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. 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000656876	SCV001742747	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000656876	SCV001807194	uncertain significance	not provided		no assertion criteria provided	clinical testing