Submissions for variant NM_000251.3(MSH2):c.1680T>C (p.Asn560=)

gnomAD frequency: 0.00043  dbSNP: rs200056411

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076241	SCV000107260	likely benign	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Synonymous substitution with no effec on splicing, tested with NMD inhibitor
GeneDx	RCV000212605	SCV000170343	benign	not specified	2013-12-18	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000126817	SCV000212795	likely benign	Hereditary cancer-predisposing syndrome	2014-07-07	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	RCV001081918	SCV000253152	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000986677	SCV000430929	uncertain significance	Lynch syndrome 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Color Diagnostics, LLC DBA Color Health	RCV000126817	SCV000684966	benign	Hereditary cancer-predisposing syndrome	2015-07-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587483	SCV000696222	benign	not provided	2016-06-27	criteria provided, single submitter	clinical testing	Variant summary: The MSH2 c.1680T>C (p.Asn560Asn) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splicing algorithms predict no change to normal splicing, and ex vivo splicing assay showed this variant does not affect splicing. This variant was found in 42/120644 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0006173 (41/66422). This frequency is greater than the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. In addition, the variant was found to co-occur with a pathogenic MSH2 variant, c.1079T>A (p.Leu360X), in one individual reported by UMD. Furthermore, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as Benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212605	SCV000889422	benign	not specified	2021-12-03	criteria provided, single submitter	clinical testing
Mendelics	RCV000986677	SCV001135740	likely benign	Lynch syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000587483	SCV001152278	likely benign	not provided	2021-05-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212605	SCV002071318	likely benign	not specified	2019-10-08	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000126817	SCV002534394	benign	Hereditary cancer-predisposing syndrome	2021-06-08	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212605	SCV002552237	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002498367	SCV002808553	likely benign	Lynch syndrome 1; Muir-Torré syndrome; Mismatch repair cancer syndrome 2	2022-03-16	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149748	SCV003838305	likely benign	Breast and/or ovarian cancer	2022-05-05	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000076241	SCV004834070	benign	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355862	SCV001550868	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH2 p.Asn560= variant was identified in the literature however the frequency of this variant in an affected population was not provided (Tournier 2008). The variant was also identified in the following databases: dbSNP (ID: rs200056411) as With Likely benign allele, ClinVar (classified as benign by GeneDx, Invitae; as likely benign by Insight, Ambry Genetics), Clinvitae (classified as benign by ClinVar; as likely benign by Invitae), UMD-LSDB (6X as neutral), Insight Colon Cancer Gene Variant Database (8X Class2), and the Insight Hereditary Tumors Database (8X Class2). The variant was not identified in COGR, Zhejiang Colon Cancer Database, and Mismatch Repair Genes Variant Database. In UMD the variant was identified with a co-occurring pathogenic MSH2 variant (c.1079T>A (p.Leu360X)), increasing the likelihood that the p.Asn560= variant does not have clinical significance. The variant was identified in control databases in 81 of 276170 chromosomes at a frequency of 0.0003 in the following populations: EuropeanNon-Finnish in 71 of 126188 chromosomes (freq. 0.001), EuropeanFinnish in 6 of 25786 chromosomes (freq. 0.0002), Latino in 2 of 34356 chromosomes (freq.0.0001), African in 1 of 24008 chromosomes (freq. 0.00004), Other in 1 of 6452 chromosomes (freq. 0.0002), increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). Functional analysis using the pCAS ex vivo splicing assay demonstrated this variant had no effect (Tournier 2008). The p.Asn560= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000587483	SCV001807293	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000587483	SCV001905768	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000587483	SCV001968429	likely benign	not provided		no assertion criteria provided	clinical testing