Submissions for variant NM_000179.3(MSH6):c.1732C>T (p.His578Tyr)

gnomAD frequency: 0.00002  dbSNP: rs768854566

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164895	SCV000215581	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-26	criteria provided, single submitter	clinical testing	The p.H578Y variant (also known as c.1732C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 1732. The histidine at codon 578 is replaced by tyrosine, an amino acid with similar properties. This variant was identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). 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.
Counsyl	RCV000663227	SCV000786425	uncertain significance	Lynch syndrome 5	2018-05-01	criteria provided, single submitter	clinical testing
Invitae	RCV001037948	SCV001201386	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164895	SCV001352796	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-17	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 578 of the MSH6 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer (PMID: 29684080). This variant has been identified in 3/281672 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.
GeneDx	RCV002255308	SCV002526600	uncertain significance	not provided	2022-06-15	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with colorectal cancer (Yehia 2018); This variant is associated with the following publications: (PMID: 21120944, 17531815, 28069802, 29684080, 27535533)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281982	SCV002570524	uncertain significance	not specified	2022-07-26	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1732C>T (p.His578Tyr) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250272 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1732C>T in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV000663227	SCV004018915	uncertain significance	Lynch syndrome 5	2023-03-28	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
All of Us Research Program, National Institutes of Health	RCV003995375	SCV004839996	uncertain significance	Lynch syndrome	2023-05-08	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 578 of the MSH6 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer (PMID: 29684080). This variant has been identified in 3/281672 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.