Submissions for variant NM_000251.3(MSH2):c.894G>C (p.Gln298His)

gnomAD frequency: 0.00002  dbSNP: rs587781397

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129243	SCV000184002	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-12	criteria provided, single submitter	clinical testing	The p.Q298H variant (also known as c.894G>C), located in coding exon 5 of the MSH2 gene, results from a G to C substitution at nucleotide position 894. The glutamine at codon 298 is replaced by histidine, an amino acid with highly similar properties. This alteration has been previously identified in an individual from a North American cohort of individuals with early onset colon cancer (Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471). This alteration was also identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000129243	SCV000685137	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-15	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with histidine at codon 298 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with early-onset colorectal cancer that was mismatch repair proficient (PMID: 27978560). This variant has also been reported in an individual affected with prostate cancer (PMID: 32832836). This variant has been identified in 2/279354 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002228472	SCV000696293	uncertain significance	not specified	2022-04-06	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.894G>C (p.Gln298His) results in a non-conservative amino acid change, located outside of, but very near to, two known functional domains (i.e. the connector domain [amino acids 156-289] and the core domain [amino acids 306-645]; InterPro) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-06 in 264848 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.894G>C has been reported in the literature in an individual affected with colon cancer (Pearlman_2016). This report does not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other 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 uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV000701906	SCV000830729	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 298 of the MSH2 protein (p.Gln298His). This variant is present in population databases (rs587781397, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 140960). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MSH2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003153414	SCV003843040	uncertain significance	Lynch syndrome 1	2023-02-16	criteria provided, single submitter	clinical testing	The MSH2 c.894G>C (p.Gln298His) missense change has a maximum subpopulation frequency of 0.0016% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. A functional assay using a massively parallel screen in human cells indicated that 18 other variants at this position are neutral (PMID: 33357406). This variant has been reported in individuals with prostate and colorectal cancer (PMID: 27978560, 32832836). To our knowledge, this variant has not been reported in individuals with constitutional mismatch repair deficiency. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Baylor Genetics	RCV003153414	SCV004196297	uncertain significance	Lynch syndrome 1	2023-08-21	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001354398	SCV004831611	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with histidine at codon 298 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with early-onset colorectal cancer that was mismatch repair proficient (PMID: 27978560). This variant has also been reported in an individual affected with prostate cancer (PMID: 32832836). This variant has been identified in 2/279354 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
True Health Diagnostics	RCV000129243	SCV000805270	uncertain significance	Hereditary cancer-predisposing syndrome	2018-04-05	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354398	SCV001549007	uncertain significance	Lynch syndrome		no assertion criteria provided	clinical testing	The MSH2 p.Gln298His variant was identified in 1 of 900 proband chromosomes (frequency: 0.001) from individuals or families with early onset CRC (Pearlman 2017). The variant was also identified in dbSNP (ID: rs587781397) as “With Likely benign, Uncertain significance allele” and ClinVar (classified as uncertain significance by Ambry Genetics, Color, Integrated Genetics, Invitae and True Health Diagnostics). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 2 of 274030 chromosomes at a frequency of 0.000007 (Genome Aggregation Database Feb 27, 2017). It was observed in the European Non-Finnish population in 2 of 125398 chromosomes (freq: 0.00002) but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The p.Gln298 variant is conserved in mammals and omputational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the His variant to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. This variant is classified as a variant of uncertain significance.