Submissions for variant NM_000179.3(MSH6):c.263G>A (p.Cys88Tyr)

gnomAD frequency: 0.00001  dbSNP: rs1060502911

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000458426	SCV000551145	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 88 of the MSH6 protein (p.Cys88Tyr). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer, colorectal cancer, and/or ovarian cancer (PMID: 30982232, 31360874, 32068069). ClinVar contains an entry for this variant (Variation ID: 410457). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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	RCV000581037	SCV000685304	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-29	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tyrosine at codon 88 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 2/251470 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in 4/13855 Chinese population samples (PMID 34172528). 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	RCV000581037	SCV001177085	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-24	criteria provided, single submitter	clinical testing	The p.C88Y variant (also known as c.263G>A), located in coding exon 2 of the MSH6 gene, results from a G to A substitution at nucleotide position 263. The cysteine at codon 88 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307505	SCV002600573	uncertain significance	not specified	2022-10-03	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.263G>A (p.Cys88Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251470 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.263G>A has been reported in the literature in individuals affected with colorectal, breast and ovarian cancer but without strong evidence for causality (example: Wang_2019, Toh_2018 and Kwong_2000). 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003470464	SCV004195810	uncertain significance	Endometrial carcinoma	2023-05-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004001835	SCV004828736	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tyrosine at codon 88 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251470 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in 4/13855 Chinese population samples (PMID 34172528). 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.