Submissions for variant NM_000251.3(MSH2):c.1122G>C (p.Gln374His)

gnomAD frequency: 0.00001  dbSNP: rs370378607

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115493	SCV000149402	uncertain significance	not provided	2014-02-20	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.1122G>C at the cDNA level, p.Gln374His (Q374H) at the protein level, and results in the change of a Glutamine to a Histidine (CAG>CAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Gln374His was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. This variant is a semi-conservative substitution in which a neutral polar amino acid is replaced with a positive polar one, altering a position that is well conserved throughout evolution and is located in the Lever domain (Lutzen 2008). Multiple in silico algorithms predict that this variant may be damaging to protein structure and function. Based on the currently available information, we consider MSH2 Gln374His to be a variant of uncertain significance.
Invitae	RCV000122979	SCV000166259	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-11-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000580948	SCV000684906	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-17	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with histidine at codon 374 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). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. In a large breast cancer case-control study, this variant has been observed in 1/60466 cases and 2/53461 unaffected controls (PMID: 33471991). This variant has been identified in 3/251402 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.
Ambry Genetics	RCV000580948	SCV001170018	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-08	criteria provided, single submitter	clinical testing	The p.Q374H variant (also known as c.1122G>C), located in coding exon 7 of the MSH2 gene, results from a G to C substitution at nucleotide position 1122. The glutamine at codon 374 is replaced by histidine, an amino acid with highly similar properties. In one study, this variant was reported in 1/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV003997266	SCV004827121	uncertain significance	Lynch syndrome	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with histidine at codon 374 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). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. In a large breast cancer case-control study, this variant has been observed in 1/60466 cases and 2/53461 unaffected controls (PMID: 33471991). This variant has been identified in 3/251402 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.