Submissions for variant NM_000251.3(MSH2):c.260C>G (p.Ser87Cys)

gnomAD frequency: 0.00003  dbSNP: rs587781447

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129363	SCV000184127	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-26	criteria provided, single submitter	clinical testing	The p.S87C variant (also known as c.260C>G), located in coding exon 2 of the MSH2 gene, results from a C to G substitution at nucleotide position 260. The serine at codon 87 is replaced by cysteine, an amino acid with dissimilar properties. This alteration was identified in a cohort of pancreatic cancer patients undergoing multigene panel testing (Young EL et al. BMC Cancer, 2018 Jun;18:697) and in a woman with primary peritoneal cancer who tested negative for the BRCA1 mutation previously identified in her family (Mitchell R et al. PLoS One, 2018 Apr;13:e0195497). This amino acid position is well 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.
GeneDx	RCV000212581	SCV000211179	uncertain significance	not provided	2018-03-06	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.260C>G at the cDNA level, p.Ser87Cys (S87C) at the protein level, and results in the change of a Serine to a Cysteine (TCT>TGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Ser87Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). MSH2 Ser87Cys is located in the mismatch binding domain (Lutzen 2008, Kansikas 2011). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available information, it is unclear whether MSH2 Ser87Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000233259	SCV000284156	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 87 of the MSH2 protein (p.Ser87Cys). This variant is present in population databases (rs587781447, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer (PMID: 32547938). ClinVar contains an entry for this variant (Variation ID: 141032). 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.
Color Diagnostics, LLC DBA Color Health	RCV000129363	SCV000685065	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-06	criteria provided, single submitter	clinical testing	This missense variant replaces serine with cysteine at codon 87 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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). This variant has been reported in individuals affected with breast, pancreatic or primary peritoneal cancers (PMID: 29659587, 29945567, 32547938). This variant has been identified in 2/282148 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.
Counsyl	RCV000662735	SCV000785507	uncertain significance	Lynch syndrome 1	2017-08-30	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662735	SCV004020254	likely benign	Lynch syndrome 1	2023-11-14	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726].
Baylor Genetics	RCV000662735	SCV004196214	uncertain significance	Lynch syndrome 1	2023-10-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997495	SCV004824251	uncertain significance	Lynch syndrome	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces serine with cysteine at codon 87 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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). This variant has been reported in individuals affected with breast, pancreatic or primary peritoneal cancers (PMID: 29659587, 29945567, 32547938). This variant has been identified in 2/282148 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.