ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.380A>G (p.Asn127Ser) (rs17217772)

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Total submissions: 18
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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,Partners HealthCare Personalized Medicine RCV000035361 SCV000059009 benign not specified 2011-12-14 criteria provided, single submitter clinical testing The Asn127Ser variant in MSH2 is not expected to have clinical significance beca use it was reported in dbSNP at a frequency ranging from ~1% to ~14% in various populations, and is most commonly observed in individuals with African ancestry (rs17217772).
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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: 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,PreventionGenetics RCV000035361 SCV000303165 benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000144619 SCV000430913 likely benign Lynch syndrome I 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 2020-12-06 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162398 SCV000685086 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000144619 SCV000744267 benign Lynch syndrome I 2015-09-21 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,VU University Medical Center Amsterdam RCV000144619 SCV000745632 benign Lynch syndrome I 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 I 2016-11-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282339 SCV000885710 benign none provided 2020-03-20 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 I 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

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