Submissions for variant NM_000251.3(MSH2):c.437G>T (p.Gly146Val)

gnomAD frequency: 0.00001  dbSNP: rs772052262

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166585	SCV000217387	likely benign	Hereditary cancer-predisposing syndrome	2022-08-22	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	RCV000205937	SCV000260599	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-07-15	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 146 of the MSH2 protein (p.Gly146Val). This variant is present in population databases (rs772052262, gnomAD 0.002%). This missense change has been observed in individual(s) with endometrial cancer (PMID: 28051113). ClinVar contains an entry for this variant (Variation ID: 186918). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 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.
Counsyl	RCV000662555	SCV000785139	uncertain significance	Lynch syndrome 1	2017-05-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166585	SCV001350531	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-14	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with valine at codon 146 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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). This variant has been reported in an individual affected with endometrial cancer, who also carried a pathogenic variant in the MSH6 gene that could explain the observed phenotype (PMID: 28051113), as well as an individual affected with ovarian cancer (PMID: 31265121). This variant has been identified in 1/251434 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.
Myriad Genetics, Inc.	RCV000662555	SCV004018266	uncertain significance	Lynch syndrome 1	2023-03-17	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000662555	SCV004196315	uncertain significance	Lynch syndrome 1	2023-08-12	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995514	SCV004830266	uncertain significance	Lynch syndrome	2024-05-30	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with valine at codon 146 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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). This variant has been reported in an individual affected with endometrial cancer, who also carried a pathogenic variant in the MSH6 gene that could explain the observed phenotype (PMID: 28051113), as well as an individual affected with ovarian cancer (PMID: 31265121). This variant has been identified in 1/251434 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.
Molecular Diagnostics Laboratory, Catalan Institute of Oncology	RCV000166585	SCV005901653	likely benign	Hereditary cancer-predisposing syndrome	2024-12-22	criteria provided, single submitter	clinical testing	PM2_Supporting, BS3, BP4, BP5 c.437G>T, located in exon 3 of the MSH2 gene, is predicted to result in the substitution of Gly by Val at codon 146, p.(Gly146Val).It is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_supporting). Computational tools for this variant suggest no significant impact on splicing and no significant impact on protein function (MAPP+PolyPhen-2 prior probability for pathogenicity: 0.0015 < 0.11 (BP4). A functional study based on cell viability assay in HEK293 or HAP1 cells using 6-TG treatment demonstrates normal function for this variant, with a LOF score -4,22 (PMID 33357406) (BS3). RT-PCR analysis of RNA with NMD-inhibition in carrier patients showed that this variant has no effect on splicing, also showing biallelic expression (r.437g>u; p.Gly146Val) (internal data). This variant has been identified in 3 patients from different families, coocurring with the germline variant MSH6 c.3955_3963del, which tumour immunohistochemistry (IHC) revealed: in the first case, a patient affected with colorectal cancer, the loss of only MSH6 protein expression; in the second case, a patient affected with endometrial cancer, the loss of MSH6 protein expression but no loss of MSH2 and tumour was MSI-H; and the third case, a patient affected with endometrial cancer, no loss of MSH2 protein expression (IHC of MSH6 was not evaluable) and tumour was MSI-H (internal data, PMID: 28051113) (BP5_Supporting). It was also identified in a patient affected with breast cancer and in a patient affected with endometrial cancer (no tumour information, internal data), and in another patient affected with ovarian cancer (PMID: 31265121). This variant has been reported in the ClinVar database (5x Uncertain Significance; 1x Likely benign), but not in Insight nor in LOVD databases. Based on currently available information, the variant c.437G>T should be considered a likely benign variant.