Submissions for variant NM_000251.3(MSH2):c.1709A>G (p.Tyr570Cys)

gnomAD frequency: 0.00001  dbSNP: rs587779963

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115506	SCV000149415	uncertain significance	not provided	2023-03-06	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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 9774676, 18822302, 21120944)
Invitae	RCV000555354	SCV000625301	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-03-09	criteria provided, single submitter	clinical testing	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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MSH2 protein function. ClinVar contains an entry for this variant (Variation ID: 127633). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant is present in population databases (rs587779963, gnomAD 0.0009%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 570 of the MSH2 protein (p.Tyr570Cys).
Ambry Genetics	RCV000574691	SCV000662247	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-17	criteria provided, single submitter	clinical testing	The p.Y570C variant (also known as c.1709A>G), located in coding exon 11 of the MSH2 gene, results from an A to G substitution at nucleotide position 1709. The tyrosine at codon 570 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been observed in at least one individual with a personal history of colorectal cancer (Lu T et al. Genet Med, 2021 Mar;23:508-515). 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.
Color Diagnostics, LLC DBA Color Health	RCV000574691	SCV000684968	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-12	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 570 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. In a large breast cancer case-control study, this variant has been reported in 3/60466 cases and 1/53461 unaffected controls (PMID: 33471991). This variant has been identified in 1/250816 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	RCV003323401	SCV004030115	uncertain significance	not specified	2023-07-10	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1709A>G (p.Tyr570Cys) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250816 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1709A>G has been reported in the literature in individuals affected with endometrial cancer and breast cancer, as well as in an unaffected control (Dorling_2021, Ring_2016). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27443514, 33471991). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003467046	SCV004196836	uncertain significance	Lynch syndrome 1	2023-05-17	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997273	SCV004834137	uncertain significance	Lynch syndrome	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 570 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. In a large breast cancer case-control study, this variant has been reported in 3/60466 cases and 1/53461 unaffected controls (PMID: 33471991). This variant has been identified in 1/250816 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.