Submissions for variant NM_000251.3(MSH2):c.944G>T (p.Gly315Val)

gnomAD frequency: 0.00006  dbSNP: rs202026056

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000781990	SCV000920446	likely benign	Lynch syndrome	2018-12-19	reviewed by expert panel	curation	Multifactorial likelihood analysis posterior probability < 0.05 (0.009)
GeneDx	RCV000034560	SCV000149459	likely benign	not provided	2020-08-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 10422993, 24082139, 22703879, 19690142, 25559809, 25203624, 26976419, 27600092, 27720647, 32849802)
Invitae	RCV001082682	SCV000254432	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000491220	SCV000580560	benign	Hereditary cancer-predisposing syndrome	2016-03-21	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034560	SCV000601496	likely benign	not provided	2023-09-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000491220	SCV000685141	likely benign	Hereditary cancer-predisposing syndrome	2018-05-23	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818212	SCV002070559	uncertain significance	not specified	2018-05-18	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000491220	SCV002526776	likely benign	Hereditary cancer-predisposing syndrome	2021-05-05	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001818212	SCV002552213	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001818212	SCV004122364	likely benign	not specified	2023-10-30	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.944G>T (p.Gly315Val) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core (IPR007696) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. c.944G>T is also close to canonical acceptor site of intron 5. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00021 in 251346 control chromosomes, predominantly at a frequency of 0.00095 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Lynch Syndrome phenotype (0.00057), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.944G>T has been reported in the literature in individuals affected with Lynch Syndrome, Hereditary Nonpolyposis Colorectal Cancer and an indiviudal without cancer history (example, Gonzalez-Garay_2013, Johnston_2012, Syngal_1999, Thompson_2020), without strong evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Thompson_2020). These results showed no damaging effect of this variant by splicing assays. The following publications have been ascertained in the context of this evaluation (PMID: 24082139, 22703879, 10422993, 32849802). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS=1, Benign/Likely Benign=8). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV004541069	SCV004773166	likely benign	MSH2-related disorder	2020-02-21	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).
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034560	SCV000043337	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355677	SCV001550629	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH2 p.Gly315Val variant was identified in 6 of 3350 proband chromosomes (frequency: 0.002) from individuals or families with Lynch Syndrome, colon cancer, or breast cancer and was not identified in 172 control chromosomes from healthy individuals (Gonzalez-Garay 2013, Johnston 2012, Mueller 2009, Pillar 2015, Syngal 1999, Tung 2016). The variant was also identified in dbSNP (ID: rs202026056) as "With Uncertain significance allele", and in ClinVar (classified as benign by Invitae, Ambry Genetics; as likely benign by GeneDx, Quest Diagnostics Nichols Institute San Juan Capistrano; as uncertain significance by Color Genomics and Biesecker Lab/Human Development Section, National Institutes of Health). The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or in Insight Hereditary Tumors Database. The variant was identified in control databases in 55 of 277094 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6464 chromosomes (freq: 0.000155), European in 3 of 126640 chromosomes (freq: 0.00002), Ashkenazi Jewish in 21 of 10152 chromosomes (freq: 0.002), and South Asian in 30 of 30778 chromosomes (freq: 0.001), while the variant was not observed in the African, Latino, East Asian, and Finnish populations. The p.Gly315 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 p.Gly315Val variant occurs in the first three bases of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. However, 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.