Submissions for variant NM_000251.3(MSH2):c.260C>A (p.Ser87Tyr)

dbSNP: rs587781447

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216857	SCV000275608	likely benign	Hereditary cancer-predisposing syndrome	2022-11-03	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.
GeneDx	RCV000235359	SCV000292909	uncertain significance	not provided	2018-05-16	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.260C>A at the cDNA level, p.Ser87Tyr (S87Y) at the protein level, and results in the change of a Serine to a Tyrosine (TCT>TAT). This variant was not observed in a cohort of individuals diagnosed with colon cancer, however it was identified in an unaffected control (Arora 2015). MSH2 Ser87Tyr was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Serine and Tyrosine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 Ser87Tyr occurs at a position that is conserved in mammals and is located in the mismatch binding domain (Lutzen 2008, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MSH2 Ser87Tyr is a pathogenic variant or a benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV001320134	SCV001510909	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-02	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002254690	SCV002526018	uncertain significance	Lynch syndrome 1	2022-03-24	criteria provided, single submitter	clinical testing	The MSH2 c.260C>A (p.Ser87Tyr) missense change has a maximum subpopulation frequency 0.0054% in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/variant/2-47635588-C-A). Seven of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in individuals with breast cancer (PMID: 32547938) and one individual with relapsed pediatric T-lymphoblastic leukemia (PMID: 32547938). To our knowledge, this variant has not been reported in individuals with Lynch syndrome or CMMRD. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_supporting, PP3.
Color Diagnostics, LLC DBA Color Health	RCV000216857	SCV004356582	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-15	criteria provided, single submitter	clinical testing	This missense variant replaces serine with tyrosine 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). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 2/250910 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.
All of Us Research Program, National Institutes of Health	RCV003997919	SCV004832127	uncertain significance	Lynch syndrome	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces serine with tyrosine 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). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 2/250910 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.