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

gnomAD frequency: 0.00011  dbSNP: rs63750684

Total submissions: 14

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: 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.
Labcorp Genetics (formerly Invitae), Labcorp	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	likely benign	Lynch syndrome 1	2024-06-20	criteria provided, single submitter	clinical testing	This variant is considered likely benign. 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].
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.
PreventionGenetics, part of Exact Sciences	RCV004734632	SCV005352519	uncertain significance	MSH2-related disorder	2024-08-13	no assertion criteria provided	clinical testing	The MSH2 c.2308A>G variant is predicted to result in the amino acid substitution p.Ile770Val. This variant was reported as heterozygous in a single control subject for a colorectal cancer study (Farrington et al. 1998. PubMed ID: 9718327) and was reported as a variant of uncertain significance in a patient with a personal or family history of breast cancer (Table 2, Pereira et al. 2022. PubMed ID: 35980532). This variant is reported in 0.028% of alleles in individuals of African descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/90955/?new_evidence=true). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.