Submissions for variant NM_000251.3(MSH2):c.972G>A (p.Gln324=)

gnomAD frequency: 0.00001  dbSNP: rs63750505

Total submissions: 14

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: 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082431	SCV000259528	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-25	criteria provided, single submitter	clinical testing
Counsyl	RCV000409097	SCV000487840	likely benign	Lynch syndrome 1	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 Diagnostics, LLC DBA Color Health	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 Laboratory Services, Illumina	RCV000409097	SCV001302368	uncertain significance	Lynch syndrome 1	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.
Sema4, Sema4	RCV000163997	SCV002526784	likely benign	Hereditary cancer-predisposing syndrome	2021-09-07	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000409097	SCV004018326	benign	Lynch syndrome 1	2023-03-21	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
PreventionGenetics, part of Exact Sciences	RCV004537299	SCV004729675	likely benign	MSH2-related disorder	2019-05-22	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000432873	SCV005090935	likely benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
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.