Submissions for variant NM_000251.3(MSH2):c.2308A>G (p.Ile770Val)

gnomAD frequency: 0.00011  dbSNP: rs63750684

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000586175	SCV000149425	likely benign	not provided	2020-09-28	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22290698, 26333163, 22949379, 18383312, 9718327, 27527004, 26810070)
Ambry Genetics	RCV000217041	SCV000274423	benign	Hereditary cancer-predisposing syndrome	2021-06-17	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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	RCV000524385	SCV000284146	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000076457	SCV000430934	uncertain significance	Lynch syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Counsyl	RCV000410216	SCV000489315	uncertain significance	Lynch syndrome 1	2016-09-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804168	SCV000696244	uncertain significance	not specified	2024-01-29	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.2308A>G (p.Ile770Val) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain of 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 1.7e-05 in 1614080 control chromosomes, predominantly at a frequency of 0.00021 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (1.7e-05 vs 0.00057), allowing no conclusion about variant significance. c.2308A>G has been reported in the literature in individuals affected with early-onset colorectal cancer and a personal and/or family history of breast cancer (examples, Farrington_1998, Pereira_2022), without strong evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrences with other pathogenic variant(s) have been reported (MSH2 c.1865C>T , p.Pro622Leu) in an internal specimen, providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not provide details for independent analysis about the variant effect (Qaddoumi_2016). The following publications have been ascertained in the context of this evaluation (PMID: 22290698, 18383312, 9718327, 35980532, 26810070). ClinVar contains an entry for this variant (Variation ID: 90955). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586175	SCV000888220	uncertain significance	not provided	2019-06-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000217041	SCV000903074	likely benign	Hereditary cancer-predisposing syndrome	2016-04-20	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000217041	SCV002534465	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-17	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000410216	SCV004018368	uncertain significance	Lynch syndrome 1	2023-03-22	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000410216	SCV004193906	uncertain significance	Lynch syndrome 1	2023-10-30	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000586175	SCV004224906	uncertain significance	not provided	2023-06-21	criteria provided, single submitter	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV000586175	SCV001749536	not provided	not provided		no assertion provided	phenotyping only	Variant interpreted as Likely benign and reported on 05-29-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.