Submissions for variant NM_000251.3(MSH2):c.991A>G (p.Asn331Asp)

gnomAD frequency: 0.00003  dbSNP: rs267607938

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000662836	SCV000107815	uncertain significance	Lynch syndrome 1	2018-06-13	reviewed by expert panel	curation	Variant reclassification due to new tumour Likelihood Ratios: Multifactorial likelihood analysis posterior probabilty is in class 3. (0.091)
Ambry Genetics	RCV000130283	SCV000185128	likely benign	Hereditary cancer-predisposing syndrome	2018-04-13	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	RCV000524429	SCV000548264	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000588648	SCV000567340	uncertain significance	not provided	2023-09-06	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 demonstrate decreased mismatch repair activity, but no effect on splicing, binding partner interaction, and nuclear localization (Tournier et al., 2008; Drost et al., 2018); Observed in individuals with colorectal or breast cancer (Spaepen et al., 2006; Tung et al., 2015); This variant is associated with the following publications: (PMID: 24362816, 22290698, 16736289, 18561205, 25871441, 25186627, 29179779, 30212499, 30504929, 21120944, 18822302)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000790630	SCV000696297	uncertain significance	not specified	2022-09-26	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.991A>G (p.Asn331Asp) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) 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 8e-06 in 251462 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. 5/5 computational tools predict no significant impact on normal splicing and ESE finder predicts that this variant may eliminate a SRp55 site and create a SRp40 site. These predictions have been tested functionally through a minigene assay which confirmed that the variant does not affect splicing, despite splicing computational tools suggesting ESE sites are predicted to be affected (Tournier_2008). However, a cell-free in vitro MMR activity assay showed that this variant had 62.4% MMR activity (Drost_2019). c.991A>G has been reported in the literature in individuals affected with Lynch Syndrome and breast cancer (Tung_2015, Tournier_2008, Spaepen_2006). One of the studies carried out additional analysis: tumor tissue from a patient was tested for microsatellite instability (0 of 10 loci were unstable), MSH2 protein expression (immunostaining showed both MSH2 and MLH1 as positive), and segregation with disease in the family (the variant did not segregate with disease in the 3 family members tested). Together, these analyses suggest the variant does not contribute to tumorigenesis (Spaepen_2006). Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2) and likely benign (n=4) including an expert panel (InSiGHT), following a recent re-classification, citing the variant as uncertain significance (originally classified as likely benign in 2013) citing new tumour Likelihood Ratios: Multifactorial likelihood analysis posterior probabilty is in class 3. (0.091). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Counsyl	RCV000662836	SCV000785694	likely benign	Lynch syndrome 1	2017-11-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130283	SCV000903282	likely benign	Hereditary cancer-predisposing syndrome	2022-01-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002483126	SCV002785089	uncertain significance	Lynch syndrome 1; Muir-Torré syndrome; Mismatch repair cancer syndrome 2	2021-07-27	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662836	SCV004018343	likely benign	Lynch syndrome 1	2023-03-21	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: 25085752].
All of Us Research Program, National Institutes of Health	RCV003997186	SCV004824531	likely benign	Lynch syndrome	2023-07-10	criteria provided, single submitter	clinical testing