Submissions for variant NM_000251.3(MSH2):c.1657A>T (p.Asn553Tyr)

gnomAD frequency: 0.00001  dbSNP: rs772772789

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000477039	SCV000548250	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 553 of the MSH2 protein (p.Asn553Tyr). This variant is present in population databases (rs772772789, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 408518). 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	RCV000774572	SCV000908312	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-13	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with tyrosine at codon 553 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251154 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	RCV000774572	SCV001173054	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-06	criteria provided, single submitter	clinical testing	The p.N553Y variant (also known as c.1657A>T), located in coding exon 10 of the MSH2 gene, results from an A to T substitution at nucleotide position 1657. The asparagine at codon 553 is replaced by tyrosine, an amino acid with dissimilar properties. In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). 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 01;108:163-175). This amino acid position is highly 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.
Sema4, Sema4	RCV000774572	SCV002534389	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-06	criteria provided, single submitter	curation
GeneDx	RCV003156243	SCV003845543	uncertain significance	not provided	2023-03-21	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; Identified in an individual with melanoma (Yehia et al., 2018); Published functional studies suggest no damaging effect: performed similar to wild type in an assay measuring resistance to 6-TG (Jia et al., 2020); This variant is associated with the following publications: (PMID: 18822302, 9774676, 21120944, 29684080, 33357406)
All of Us Research Program, National Institutes of Health	RCV004000787	SCV004834015	uncertain significance	Lynch syndrome	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with tyrosine at codon 553 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251154 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.