ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.972G>A (p.Gln324=) (rs63750505)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076769 SCV000107809 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Synonymous substitution with no effect on splicing tested with NMD inhibitor
Ambry Genetics RCV000163997 SCV000214600 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: 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 RCV001082431 SCV000259528 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-02 criteria provided, single submitter clinical testing
Counsyl RCV000409097 SCV000487840 likely benign Lynch syndrome I 2015-11-20 criteria provided, single submitter clinical testing
GeneDx RCV000524427 SCV000513656 likely benign not provided 2021-04-12 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 10777691)
Color Health, Inc RCV000163997 SCV000685145 benign Hereditary cancer-predisposing syndrome 2015-05-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000432873 SCV000919693 benign not specified 2018-03-23 criteria provided, single submitter clinical testing Variant summary: MSH2 c.972G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Lynch Syndrome phenotype (0.00057), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The c.972G>A has been reported in the literature in individuals affected with Lynch Syndrome. These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (MLH1 c.676C>T, p.R226*), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000524427 SCV001134382 likely benign not provided 2018-12-27 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000409097 SCV001302368 uncertain significance Lynch syndrome I 2018-01-13 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357930 SCV001553537 likely benign Carcinoma of colon no assertion criteria provided clinical testing The MSH2 p.Gln324= variant was identified in 1 of 30 proband chromosomes (frequency: 0.03) from individuals or families with colorectal cancer and was not identified in 284 control chromosomes from healthy individuals (Nomura 2000). The variant was also identified in dbSNP (ID: rs63750505) as With Likely benign allele, ClinVar (classified as benign by Invitae, and as likely benign by InSIGHT, Ambry Genetics, Counsyl, and Gene Dx), Clinvitae (classified as likely benign by ClinVar; as benign by Invitae), Insight Colon Cancer Gene Variant Database (4X class2), Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors Database (4X class 2). The variant was not identified in Cosmic, UMD-LSDB, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 21 of 277184 chromosomes at a frequency of 0.000076 in following populations: Asian in 16 of 18866 chromosomes (freq. 0.001), European in 3 of 126678 chromosomes (freq. 0.00002), Latino in 2 of 34416 chromosomes (freq. 0.0001) increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Gln324= 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. However, 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing (loss of a cryptic splice site); this is not very predictive of pathogenicity. 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.

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