Submissions for variant NM_000251.3(MSH2):c.380A>G (p.Asn127Ser)

gnomAD frequency: 0.02317  dbSNP: rs17217772

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000030253	SCV000107622	no known pathogenicity	Lynch syndrome	2013-09-05	reviewed by expert panel	research	MAF >1%
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035361	SCV000059009	benign	not specified	2022-05-11	criteria provided, single submitter	clinical testing	The p.Asn127Ser variant in MSH2 is classified as benign because it has been identified in 7.8% (1942/24960) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as Benign on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 36577). ACMG/AMP Criteria applied: BA1.
Eurofins Ntd Llc (ga)	RCV000035361	SCV000203031	benign	not specified	2014-04-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162398	SCV000212723	benign	Hereditary cancer-predisposing syndrome	2014-11-18	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.
PreventionGenetics, part of Exact Sciences	RCV000035361	SCV000303165	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000144619	SCV000430913	likely benign	Lynch syndrome 1	2018-01-23	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Invitae	RCV000757470	SCV000559220	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162398	SCV000685086	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000144619	SCV000744267	benign	Lynch syndrome 1	2015-09-21	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000144619	SCV000745632	benign	Lynch syndrome 1	2016-12-11	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000144619	SCV000781768	uncertain significance	Lynch syndrome 1	2016-11-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001353586	SCV000885710	benign	not provided	2023-11-28	criteria provided, single submitter	clinical testing
GeneDx	RCV001353586	SCV001891611	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 14574163, 28932927, 24728327, 27629256, 26951660, 27884173, 12624141, 20176959, 16237223, 18470917, 22949387, 18951462, 21120944, 17720936, 11606497, 25107687, 21056691, 18547406)
Sema4, Sema4	RCV000162398	SCV002534515	benign	Hereditary cancer-predisposing syndrome	2020-02-06	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000035361	SCV002552195	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490419	SCV002797244	likely benign	Lynch syndrome 1; Muir-Torré syndrome; Mismatch repair cancer syndrome 2	2022-04-23	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149584	SCV003837615	benign	Breast and/or ovarian cancer	2021-07-02	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000144619	SCV004015938	benign	Lynch syndrome 1	2023-07-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000030253	SCV004830122	benign	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030253	SCV000052920	benign	Lynch syndrome	2011-12-21	no assertion criteria provided	clinical testing
ITMI	RCV000035361	SCV000085761	not provided	not specified	2013-09-19	no assertion provided	reference population
Pathway Genomics	RCV000144619	SCV000189946	benign	Lynch syndrome 1	2014-07-24	no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000035361	SCV000257187	benign	not specified		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353586	SCV000592462	likely benign	not provided		no assertion criteria provided	clinical testing	The MSH2 p.Asn127Ser variant was identified in the literature in black, white and Hispanic populations with functional studies suggesting that the p.Asn127Ser variant, in isolation, does not compromise MMR. However in 2 studies, this variant was identified together with other missense substitutions (especially p.Ala328Pro), and demonstrated significantly decreased repair deficiency (Kantelinen 2012, Ollila 2008, Samowitz 2001). The variant was also identified in dbSNP (ID: rs17217772) “With benign, uncertain significance allele” and is listed in the 1000 Genomes Project in 124 of 5000 chromosomes (frequency: 0.0248). The variant is also identified in the NHLBI Exome Sequencing Project (ESP) in 4 of 8600 European American (frequency: 00005) and in 339 of 4406 African American alleles (frequency: 0.077). The variant is listed in the Exome Aggregation Consortium (ExAC) database (released Mar 14, 2016) and identified in 848 of 121398 chromosomes of which 27 were homozygous (frequency: 0.007) or 791 of 10402 Africans (frequency: 0.076), 20 of 11578 Latino (frequency: 0.002), 29 of 66732 European (Non-Finish) (frequency: 0.0004), 4 of 16510 South Asian (frequency: 0.0002) and 4 in 908 (frequency: 0.004) in other, increasing the likelihood this could be a low frequency benign variant. The variant is listed in GeneInsight - COGR (1x as benign by LMM and 2x as benign by ARUP); ClinVar (listed as benign by InSIGHT, Laboratory for Molecular Medicine, Emory Genetics, Ambry Genetics, Mayo Clinic, Pathway Genomics LabCorp and by TMI with no clinical significance given); in Clinvitae (by EmyClass 1x as benign) and InSiGHT Colon Cancer Gene Variant Databases (LOVD) 34x as Class 1 - not pathogenic. In UMD, the variant was identified 23x as neutral with a co-occurring pathogenic MLH1 p.Pro649LeufsX12, increasing the likelihood that the p.Asn127Ser variant does not have clinical significance. The p.Asn127 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Asn127Ser variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict the abolishment of the consensus splice site; however, HumanSpliceFinder and MaxEntScan predict an altered 3' splice site in this region and we cannot eliminate the possibility of a novel cryptic splice site. 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.
True Health Diagnostics	RCV000162398	SCV000788037	benign	Hereditary cancer-predisposing syndrome	2017-10-10	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000035361	SCV001799601	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000035361	SCV001906115	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000035361	SCV001923645	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000035361	SCV001958444	benign	not specified		no assertion criteria provided	clinical testing