Submissions for variant NM_000251.3(MSH2):c.1927G>A (p.Glu643Lys)

gnomAD frequency: 0.00001  dbSNP: rs374840361

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000589876	SCV000211192	uncertain significance	not provided	2022-12-19	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies are inconclusive: increased mutation rate compared to wild type controls in a yeast based assay (Ollodart et al., 2020); Observed in individuals with a personal history of ovarian cancer or pancreatic ductal adenocarcinoma (Pal et al., 2012; Shindo et al., 2017; Hu et al., 2020); This variant is associated with the following publications: (PMID: 25637381, 23047549, 28767289, 32659497, 27535533, 18822302, 21120944, 33848333)
Ambry Genetics	RCV000160596	SCV000216735	likely benign	Hereditary cancer-predisposing syndrome	2023-04-03	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.
Invitae	RCV000204646	SCV000261595	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160596	SCV000690031	uncertain significance	Hereditary cancer-predisposing syndrome	2021-03-09	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 643 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). However, a functional study has reported that this variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (PMID: 33357406). This variant has been reported in one individual each affected with ovarian cancer (PMID: 23047549) and pancreatic cancer (PMID: 28767289, 32659497). This variant has also been observed in trans with a pathogenic whole gene deletion of the MSH2 gene in an individual affected with an unspecified gynecological cancer (ClinVar variation ID 161299). This variant has been identified in 4/251452 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	RCV002509245	SCV000696229	uncertain significance	not specified	2022-12-12	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1927G>A (p.Glu643Lys) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251452 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1927G>A has been reported in individuals affected with Ovarian Cancer and Pancreatic Cancer, however these reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome (Pal_2012, Shindo_2017). One publication using the yeast ortholog of the variant showed a modest increase in random mutation rates in a continuous culture assay (Ollodart_2021). The increase in mutation rates observed did not indicate loss of function, therefore not allowing for convincing conclusions about the variant on protein function. Five ClinVar submitters have assessed the variant since 2014: four classified the variant as uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV000765671	SCV000897013	uncertain significance	Lynch syndrome 1; Mismatch repair cancer syndrome 1; Muir-Torré syndrome	2018-10-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532666	SCV004120695	uncertain significance	MSH2-related disorder	2023-01-11	criteria provided, single submitter	clinical testing	The MSH2 c.1927G>A variant is predicted to result in the amino acid substitution p.Glu643Lys. This variant was reported in an individual with ovarian cancer and an individual with pancreatic adenocarcinoma (Table 2, Pal et al. 2012. PubMed ID: 23047549; Table A2, Shindo et al. 2017. PubMed ID: 28767289). This variant is reported in 4 of ~251,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/2-47702331-G-A; Table S1, Amendola et al. 2015. PubMed ID: 25637381) and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/161299/643). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589876	SCV004220964	uncertain significance	not provided	2022-10-17	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000035 (4/113736 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with ovarian cancer (PMID: 23047549 (2012)) and pancreatic cancer (PMID: 32659497 (2020), 28767289 (2017)). A yeast based functional study has reported inconclusive findings regarding the effect on this variant on MSH2 protein function (PMID: 33848333 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV003998170	SCV004825006	uncertain significance	Lynch syndrome	2023-06-28	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 643 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). However, a functional study has reported that this variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (PMID: 33357406). This variant has been reported in one individual each affected with ovarian cancer (PMID: 23047549) and pancreatic cancer (PMID: 28767289, 32659497). This variant has also been observed in trans with a pathogenic whole gene deletion of the MSH2 gene in an individual affected with an unspecified gynecological cancer (ClinVar variation ID 161299). This variant has been identified in 4/251452 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.
CSER _CC_NCGL, University of Washington	RCV000148637	SCV000190352	uncertain significance	Ovarian cancer	2014-06-01	no assertion criteria provided	research
GenomeConnect - Invitae Patient Insights Network	RCV003483522	SCV004228709	not provided	Lynch syndrome; Mismatch repair cancer syndrome 2		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 04-20-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.